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Baseline characteristics of children in the International PANS Registry (IPR) Epidemiology Study

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Purpose The International PANS Registry (IPR) Epidemiology Study is a registry-based, longitudinal study. We designed this study to improve phenotyping and characterisation of children with paediatric acute-onset neuropsychiatric syndrome (PANS) and PANS-like features and facilitate multidisciplinary and translational health research. This cohort provides new opportunities to address unresolved research questions related to the broad spectrum of heterogenous PANS-like conditions. Participants Inclusion in the IPR Epidemiology Study remains open indefinitely via IPR enrolment online. Participants include children with PANS or who have PANS-like features and their healthy siblings. We collected cross-sectional survey data based on parent report, including details on phenotypic traits and characteristics that, to our knowledge, have not been previously collected for this patient population. We describe the baseline characteristics of cases and their healthy siblings here. Findings to date The IPR Epidemiology Study currently includes 1781 individuals (1179 cases, 602 siblings; from 1010 households). Many households include a sibling (n=390, 39%) and some include multiple cases (n=205, 20%). Mean enrolment age was 11.3±4.3 years for cases and 10.1±5.3 for siblings. Leading PANS-like features include anxiety (94%), emotional lability (92%) and obsessions (90%). Onsets were sudden and dramatic (27%), gradual with a subsequent sudden and dramatic episode (68%) or a gradual progression (5%). The mean age at early signs/symptom onset was 4 years and 7 years at sudden and dramatic increases, respectively. Infection/illness was the most common suspected symptom trigger (84%). Nearly all cases had been treated with antibiotics (88%) and/or non-steroidal anti-inflammatory drugs (79%). Parents reported immune-related conditions in cases (18%) and their nuclear, biological family (48%; 39% in biological mothers). Future plans Future plans include increasing sample size, collecting longitudinal survey data, recruiting appropriate study controls and expanding the scope of the database, prioritising medical record data integration and creating a linked biorepository. Secondary data analyses will prioritise identifying subgroups by phenotypic traits, maternal health and disease characteristics.
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MastersonEE, GavinJM. BMJ Open 2024;14:e072743. doi:10.1136/bmjopen-2023-072743
Open access
Baseline characteristics of children in
the International PANS Registry (IPR)
Epidemiology Study
Erin E Masterson ,1 Jessica M Gavin2
To cite: MastersonEE,
GavinJM. Baseline
characteristics of children in the
International PANS Registry (IPR)
Epidemiology Study. BMJ Open
2024;14:e072743. doi:10.1136/
bmjopen-2023-072743
Prepublication history and
additional supplemental material
for this paper are available
online. To view these les,
please visit the journal online
(http://dx.doi.org/10.1136/
bmjopen-2023-072743).
Received 13 February 2023
Accepted 21 December 2023
1Environmental and
Occupational Health Sciences,
University of Washington,
Seattle, Wisconsin, USA
2Pediatric Research and
Advocacy Initiative, Richmond,
Virginia, USA
Correspondence to
Dr Erin E Masterson;
emaster@ uw. edu
Cohort profile
© Author(s) (or their
employer(s)) 2024. Re- use
permitted under CC BY- NC. No
commercial re- use. See rights
and permissions. Published by
BMJ.
ABSTRACT
Purpose The International PANS Registry (IPR)
Epidemiology Study is a registry- based, longitudinal
study. We designed this study to improve phenotyping
and characterisation of children with paediatric acute-
onset neuropsychiatric syndrome (PANS) and PANS- like
features and facilitate multidisciplinary and translational
health research. This cohort provides new opportunities
to address unresolved research questions related to the
broad spectrum of heterogenous PANS- like conditions.
Participants Inclusion in the IPR Epidemiology Study
remains open indenitely via IPR enrolment online.
Participants include children with PANS or who have
PANS- like features and their healthy siblings. We collected
cross- sectional survey data based on parent report,
including details on phenotypic traits and characteristics
that, to our knowledge, have not been previously collected
for this patient population. We describe the baseline
characteristics of cases and their healthy siblings here.
Findings to date The IPR Epidemiology Study currently
includes 1781 individuals (1179 cases, 602 siblings;
from 1010 households). Many households include a
sibling (n=390, 39%) and some include multiple cases
(n=205, 20%). Mean enrolment age was 11.3±4.3 years
for cases and 10.1±5.3 for siblings. Leading PANS- like
features include anxiety (94%), emotional lability (92%)
and obsessions (90%). Onsets were sudden and dramatic
(27%), gradual with a subsequent sudden and dramatic
episode (68%) or a gradual progression (5%). The mean
age at early signs/symptom onset was 4 years and 7 years
at sudden and dramatic increases, respectively. Infection/
illness was the most common suspected symptom trigger
(84%). Nearly all cases had been treated with antibiotics
(88%) and/or non- steroidal anti- inammatory drugs (79%).
Parents reported immune- related conditions in cases
(18%) and their nuclear, biological family (48%; 39% in
biological mothers).
Future plans Future plans include increasing sample size,
collecting longitudinal survey data, recruiting appropriate
study controls and expanding the scope of the database,
prioritising medical record data integration and creating a
linked biorepository. Secondary data analyses will prioritise
identifying subgroups by phenotypic traits, maternal health
and disease characteristics.
INTRODUCTION
Complex, neuropsychiatric conditions
suspected of involving the immune system
are not well understood, causing children
to suffer from devastating, long- term psychi-
atric and neurological problems; academic,
developmental and behavioural regression;
and severe social and emotional disruption
to patients and their families.1–5 Severe cases
have led to in- patient hospitalisation and
death.6 Paediatric acute- onset neuropsychi-
atric syndrome (PANS) is one such syndrome
that is not well defined, but characterised
by a sudden onset of obsessive–compulsive
disorder (OCD) and/or severely restricted
food intake and at least two other neuro-
psychiatric symptoms in previously healthy
children.3–5 These may include anxiety,
emotional lability, irritability/aggression,
behavioural regression, deterioration in
school performance, sensory and/or motor
abnormalities, and somatic signs and symp-
toms.3 These symptoms tend to present in
flare episodes. They are thought to follow a
challenge to the immune system, triggered
by exposure to infectious or other environ-
mental factors and related to underlying
immune dysregulation.7 Other names that
STRENGTHS AND LIMITATIONS OF THIS STUDY
The main strength of this study is that it draws from
the International PANS Registry (IPR) database, the
rst centralised, large- scale epidemiologic registry
for patients with paediatric acute- onset neuropsy-
chiatric syndrome (PANS) and those with PANS- like
features and their families.
The IPR Epidemiology Study was designed to phe-
notypically characterize participants and follow
them longitudinally.
The IPR Epidemiology Study includes children who
have PANS as well as those who have PANS- like
features but may not meet the current working
criteria and their siblings, who may develop PANS
symptoms in the future.
All data are based on parental self- report and sub-
ject to recall bias.
To date, the convenient sample of participants is not
generalisable or representative of any region, demo-
graphic, nor specic patient population.
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Open access
have been used to classify patients with related condi-
tions include: paediatric infection- triggered autoimmune
neuropsychiatric disorder, paediatric autoimmune neuro-
psychiatric disorders associated with streptococcal infec-
tions (PANDAS),8–10 childhood acute neuropsychiatric
symptoms, postinfectious or autoimmune basal ganglia
encephalitis, autoimmune OCD and children’s postinfec-
tious autoimmune encephalopathy.
PANS is a neuropsychiatric condition that may involve
underlying neuroimmune pathophysiology.4 11 PANS
is likely an ‘umbrella’ term for a broad, heterogenous
syndrome comprised of definable subgroups that relate
to causal factors, mechanistic pathways, disease course
and treatment response.12 13 One known subgroup of
PANS is related to a group strep A infection specifi-
cally: PANDAS.2 8 14 PANS- related conditions typically
follow a relapsing- remitting clinical course with flares
in psychiatric and physical symptoms typically lasting
3–4 months.15 16 Some patients develop a chronic illness
course that requires ongoing treatment.17 Case manage-
ment often involves long and multiple courses of treat-
ment that target the psychiatric and physical symptoms,
the source of the inflammation and the disturbance of
the immune system.18 Although some patients’ symp-
toms go into remission, there is no established cure for
PANS.
Causal factors for PANS are suspected to include
bacterial and viral infections and other factors, such as
genetics, environmental factors and metabolic disor-
ders.11 The underlying biological mechanism linking
infection and neuropsychiatric symptoms is hypothesised
to be an autoimmune reaction, in which an abnormal
immune response and/or dysregulation in the immune
system causes damage to the brain tissue due to cross-
reactive antibodies.19 PANS is observed in siblings and
family clusters, suggesting genetic predisposition and
environmental triggers may play important roles.20–23
Early genetic evidence further supports an association
with PANS.24 25 Due to vague specification of the condi-
tion and a void of population- based data, the prevalence
of these PANS- related neuroimmune conditions is not
currently known.
A void of standardized, large- scale data on the broad
spectrum of children and families affected by PANS and
PANS- like features has hindered advancement of scien-
tific knowledge relating to the underlying heterogeneity,
pathophysiology, biomarker discovery, therapeutic targets
for novel drug discovery, and ultimately, disease preven-
tion.26 To date, one large- scale survey has been completed
(n=698), but it did not include longitudinal follow- up and
it restricted inclusion to those who had reportedly been
diagnosed with PANS or PANDAS.15 Several small clin-
ical study samples from specialty treatment centres in the
USA and Sweden have also been described according to
their phenotypic characteristics and clinical presentation,
but these focus on patients who meet the current restric-
tive working criteria, requiring patients have an ‘abrupt,
dramatic onset’ of symptoms.5 8 14 16 27 28
These gaps in knowledge systematically result in
adverse repercussions for patients and their families,
including undetected disease, mis or delayed diagnosis,
inappropriate and/or delayed treatment and contribute
to existing controversy around these conditions. Individ-
uals from families with low socioeconomic position are
likely particularly disadvantaged in this regard given care-
seeking at specialty PANS clinics often requires families
to cross state lines and pay medical costs out of pocket.
The International PANS Registry (IPR) was created to
facilitate and accelerate multidisciplinary and transla-
tional health research focused on this patient population,
including but not limited to immunology, rheuma-
tology, microbiology, psychiatry, neurology and genetics.
The embedded IPR Epidemiology Study is an ongoing,
registry- based, longitudinal, observational study that is, to
our knowledge, the largest study sample of children with
PANS and PANS- like features and their healthy siblings.
In this paper, we describe the cross- sectional, baseline
data of the first 1781 study participants.
Cohort description
Study design and protocol
The IPR Epidemiology Study is an ongoing, registry-
based, longitudinal, observational study by which we will
investigate the epidemiology of the broad spectrum of
PANS- related conditions. The IPR rationale and study
protocol is described elsewhere (manuscript under
review). To date, the IPR Epidemiology Study includes
survey data based on parent report for suspected PANS
cases and their siblings. We designed the IPR Epidemi-
ology Study to enable ongoing contact with participants
and to facilitate ancillary studies and integration of new
data elements in the future. Study participants will be
invited to participate in periodic follow- up surveys to
track longitudinal observations on all cases and siblings;
siblings will be asked to report development of any new
PANS- like features (online supplemental figure 1).
Participants and eligibility criteria
Children, adolescents and adults in the USA and Canada
suspected to have/had PANS or PANS- like features and
their siblings who are not currently affected by these
conditions are welcome to enrol in the IPR. We recruited
patients by convenient sampling directing interested
parties to the publicly accessible link on the IPR’s website,
using Facebook, mailing lists (including emails and news-
letters), partnerships with other non- profit organisations,
clinical referral networks, local community events, and
international conferences.
The IPR Epidemiology Study participants are a subsa-
mple of the IPR Recruitment Pool. Inclusion criteria for
the IPR Epidemiology Study is completion of the following
baseline surveys: household introduction and demographic
surveys and the individual eligibility, demographics, maternal
health, prenatal/perinatal/postnatal periods and comorbidities
surveys; cases are additionally required to complete the
diagnosis, symptoms and onset surveys. Individuals (cases
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Open access
Table 1 Child participant demographics (N=1781)
Cases (n=1179) Siblings (n=602)
Age at enrolment* 11.3 (SD: 4.3) 10.1 (SD: 5.3)
Sex
Male 676 (57%) 317 (53%)
Female 502 (43%) 285 (47%)
Neither 1 (<1%) 0
Singleton versus multiple gestation birth
Singleton 1105 (94%) 561 (93%)
Twin 56 (5%) 33 (5%)
Triplet 5 (<1%) 2 (<1%)
Unknown 13 (1%) 6 (1%)
Highest grade completed at enrolment
Never attended/kindergarten only 158 (13%) 168 (28%)
First 87 (7%) 41 (7%)
Second 94 (8%) 38 (6%)
Third 109 (9%) 33 (5%)
Fourth 112 (10%) 35 (6%)
Fifth 111 (9%) 43 (7%)
Sixth 103 (9%) 48 (8%)
Seventh 101 (9%) 32 (5%)
Eighth 78 (7%) 44 (7%)
At least ninth 226 (19%) 120 (20%)
Family’s total income (before taxes) during the 12 months before the child was born, including wages, salaries, social security, retirement
benets, help from relatives, etc.
US$0–US$16 000 16 (1%) 13 (2%)
US$16 001–US$20 000 7 (1%) 3 (<1%)
US$20 001–US$24 000 15 (1%) 1 (<1%)
US$24 001–US$28 000 11 (1%) 5 (1%)
US$28 001–US$32 000 19 (2%) 9 (2%)
US$32 001–US$40 000 39 (3%) 26 (4%)
US$40 001–US$48 000 42 (4%) 20 (3%)
US$48 001–US$57 000 50 (4%) 28 (5%)
US$57 001–US$60 000 44 (4%) 20 (3%)
US$60 001–US$73 000 79 (7%) 31 (5%)
US$73 001–US$85 000 104 (9%) 52 (9%)
US$85 001–US$100 000 137 (12%) 78 (13%)
US$100 001–US$125 000 152 (13%) 69 (11%)
US$125 001–US$150 000 102 (9%) 69 (11%)
US$150 001–US$175 000 88 (7%) 29 (5%)
US$175 001–US$200 000 41 (3%) 18 (3%)
US$200 001–US$250 000 50 (4%) 22 (4%)
US$250 001–US$300 000 22 (2%) 10 (2%)
US$300 000 or more 34 (3%) 28 (5%)
Missing /I prefer not to respond 127 (11%) 71 (12%)
Insurance †
Private insurance 913 (80%) NA
Medicaid 145 (13%) NA
Canadian government healthcare 96 (8%) NA
Continued
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and siblings) may be included in the IPR Epidemiology
Study even if their household members are not. House-
holds are designated as ‘complete household inclusion’
when all individual members enrolled in the IPR from
one household have met the Epidemiology Study inclu-
sion criteria.
The data described here were collected using the
Dacima Software platform.
Patient and public involvement
The IPR and embedded Epidemiology Study are based
in a collaborative community- based research partner-
ship between the two authors, an epidemiologist (EM)
and the director of the IPR sponsor (JG), the Pediatric
Research and Advocacy Initiative (PRAI). PRAI, a non-
profit organisation supported by the parent/patient
community raised funds from families affected by PANS
and related conditions to fund the establishment of the
first registry for families affected by PANS and related
conditions. Many of the survey question responses we
describe in this manuscript were originally developed
via parent discussions and interactions on social media
and inquired about via informal polling in online parent
support groups. Through these platforms, thousands of
families from around the world were able to compare
notes on common clinical reports, histories and presen-
tations they observed in their children who they suspect
have PANS. JG led the initial compilation of these ques-
tions and topics and EM guided their conversion into a
formal set of surveys. This is the first study that addresses
their collective desire for these topics to be further inves-
tigated and more deeply considered in the scientific and
clinical communities.
Statistical analyses
In this paper, we describe the IPR Epidemiology Study
subsample, including their individual and household
demographics; neurologic, psychiatric and behavioural
symptoms; symptom onset; phenotypic and other char-
acteristics; phenotypic traits and other characteristics;
comorbid conditions; treatment and medication expe-
rience; family health history; disease impact and experi-
ence; and interest in sharing existing data and making
additional data contributions. We use descriptive statis-
tics, including means and SD to describe continuous
measures and frequencies and proportions to describe
categorical measures. We stratify descriptions by cases
and siblings. Analyses were conducted in SAS V.9.4 (SAS
Institute, Cary, North Carolina, USA).
FINDINGS TO DATE
IPR Epidemiology Study participant prole
Data collection cut- off for this report was December
2021. At this point in time, 1781 participants met the
inclusion criteria for the IPR Epidemiology Study. The
IPR Epidemiology Study includes 1010 households, 1179
cases and 602 siblings. Nearly all adult respondents were
the primary caregiver of the child(ren) they enrolled in
the study (99% of cases, 98% of siblings) and primarily
biological mothers (94% of cases and 93% of siblings). At
the time of enrolment, cases were older than the enrolled
siblings. Most participants were under 18 years of age
(94%), though adults whose parent has power of attorney
are also included (table 1, online supplemental figure 2).
Most (81%) of the cases report that a physician has told
them their child has PANS and/or PANDAS.
Cases (n=1179) Siblings (n=602)
Race
White (ie, European, Middle Eastern, Northern Africa, etc) 983 (95%) 516 (95%)
More than one race or origin 137 (12%) 58 (10%)
Asian (ie, Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese, Hmong, Laotian, Thai,
Pakistani, Cambodian, etc)
23 (2%) 14 (3%)
Black or African American (ie, African American, Haitian, Nigerian, etc) 3 (<1%) 2 (<1%)
American Indian or Alaskan Native (ie, Navajo, Mayan, Tlingit, etc) 9 (1%) 2 (<1%)
Native Hawaiian or other Pacic Islander (ie, Native Hawaiian, Guamanian or Chamorro,
Samoan, Fijian, Tongan, etc)
1 (<1%) 0
Other race or origin 4 (<1%) 3 (<1%)
Missing 2 0
Ethnicity
Hispanic, Latino or Spanish origin (ie, Mexico, Mexican American, Puerto Rican, Cuban,
Argentinian, Colombian, Dominican, Nicaraguan, Salvadorian, Spaniard, etc)
84 (7%) 34 (6%)
n (%) or mean (SD).
*Missing n=6 sibling date of births.
†Missing n=35 cases; ≤3% of cases reported coverage from each of the following: Medicare, Medi- gap, SCHIP (CHIP/Children’s Health Insurance
Program), Military healthcare (Tricare/VA/CHAMP- VA), Indian Health Service, State- sponsored health plan, other government programme, single
service plan (eg, dental, vision, prescriptions), no coverage of any kind, other coverage (not listed here).
Table 1 Continued
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Table 2 Neurologic, psychiatric and behavioural symptoms by parent report, N=1179
Anxiety (eg,
separation
anxiety, irrational
fears)
Any anxiety 1109 (94%)
Initial onset felt abrupt and dramatic 833 (75%)
Generalised anxiety (worrying) 963 (87%)
Separation anxiety 874 (79%)
Phobias or irrational fears 795 (72%)
Panic attacks (with feelings of terror or dread and physical symptoms, such as dilated pupils, racing heart
and dry mouth)
640 (58%)
A ‘terror- stricken look’ as part of his or her regular countenance 460 (41%)
Emotional
lability (eg,
mood changes,
depression)
Any emotional lability 1086 (92%)
Initial onset felt abrupt and dramatic 845 (78%)
Sudden and unexpected changes in mood 907 (84%)
Rages when upset 849 (78%)
Generally emotionally labile 774 (72%)
Inner sense of restlessness and agitation 757 (70%)
Suicidal ideation 379 (35%)
Self- injurious behaviours 382 (35%)
Clinical depression 332 (31%)
Dissociation (disconnecting from one’s thoughts, feelings, memories or sense of identity) 289 (27%)
Obsessions
(unwanted
thoughts, fears
and recurring
worries)
Any obsessions 1057 (90%)
Initial onset felt abrupt and dramatic 759 (72%)
Aggressive harm to oneself or others 518 (49%)
Need for symmetry or exactness (perfectionism) 510 (48%)
Perfectionism in performance (including need for straight as in school, inability to lose) 433 (41%)
Somatic obsessions (swallowing, breathing, blinking, etc) 373 (35%)
Contamination 371 (35%)
Hoarding/saving 347 (33%)
Moral or religious (scrupulously) 183 (17%)
Sexual 144 (14%)
Somatic signs
and symptoms
(eg, sleep
disturbance
and urinary
symptoms)
Any somatic signs and symptoms 986 (84%)
Initial onset felt abrupt and dramatic 713 (72%)
Sleep disturbance: difculty falling asleep (initial insomnia) 605 (61%)
Urinary symptoms: daytime urinary frequency increase/urgency to void, without evidence of a urinary tract
infection
491 (50%)
Sleep disturbance: difculty staying asleep (middle insomnia) 404 (41%)
Sleep disturbance: waking up too early (terminal insomnia) 402 (41%)
Sleep disturbance: night terror 377 (38%)
Urinary symptoms: new onset of night- time bedwetting (secondary enuresis) 377 (32%)
Irritability,
aggression,
severe
oppositional
behaviours
Any irritability, aggression, severe oppositional behaviours 983 (83%)
Initial onset felt abrupt and dramatic 764 (78%)
Child demonstrates remorse after an ‘irritable, aggressive or severe oppositional behaviour’ outburst
Always 306 (31%)
Occasionally 369 (38%)
Usually 229 (29%)
Never 79 (8%)
Irritability 931 (95%)
Yelling 777 (79%)
Aggression (without provocation or precipitant) 675 (69%)
Severely oppositional behaviours 648 (66%)
Growling 393 (40%)
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Sensory
abnormalities
(eg, unusual
sensitivity of the
senses)
Any sensory abnormalities 951 (81%)
Initial onset felt abrupt and dramatic 597 (63%)
Sensitivity to noises/sounds 752 (79%)
Sensitivity to textures 632 (66%)
Sensory seeking behaviours (needing to touch or feel particular objects or textures) 544 (57%)
Sensitivity to smells 513 (54%)
Sensitivity to temperature (heat or cold) 494 (52%)
Sensitivity to light 486 (51%)
Sensitivity to tastes 441 (46%)
Visual or auditory hallucinations (including frightening images and altered perceptions) 368 (39%)
Distortions of visual perceptions 233 (25%)
Compulsions
(repetitive
behaviours and
rituals)
Any compulsions 937 (79%)
Initial onset felt abrupt and dramatic 670 (72%)
Mental 516 (55%)
Repeating rituals 487 (52%)
Rdering/arranging (perfectionism) 418 (45%)
Checking 405 (43%)
Cleaning/washing 299 (32%)
Hoarding 280 (30%)
Counting 228 (24%)
Deterioration
in school
performance (eg,
decit of certain
skills, shortened
attention span)
Any deterioration in school performance 927 (79%)
Initial onset felt abrupt and dramatic 673 (73%)
Concentration difculties (impulsivity, inattention and motoric hyperactivity) 840 (91%)
Shortened attention span 791 (85%)
Decit of math skill 601 (65%)
Memorisation difculties 595 (64%)
Decit of visuospatial skills 393 (42%)
Motor
abnormalities
(eg, tics,
clumsiness,
motoric
hyperactivity,
speech
disorders)
Any motor abnormalities 860 (73%)
Initial onset felt abrupt and dramatic 656 (76%)
Tics 654 (76%)
Handwriting deterioration (dysgraphia) 581 (68%)
Akathisia (restlessness) 402 (47%)
Clumsiness 370 (43%)
Motoric hyperactivity 360 (42%)
Palilalia (a speech disorder characterised by involuntary repetition of words, phrases or sentences) 267 (31%)
Choreiform movements (‘ne, piano- playing movements of the ngers’ that present only when the child
maintains stressed postures such as arms stretched straight out, hands extended)
213 (25%)
Stuttering 172 (20%)
Behavioural
(developmental)
regression (eg,
‘baby talk’,
temper tantrums
and ‘clingyness’)
Any behavioural (developmental) regression 855 (73%)
Initial onset felt abrupt and dramatic 674 (79%)
Separation anxiety (‘clingy’ to a parent) 708 (83%)
Throwing temper tantrums 667 (78%)
Loss of age- appropriate language (including talking ‘baby talk’) 499 (58%)
High- pitch squealing/screeching 420 (49%)
Table 2 Continued
Continued
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Case and sibling participants are mostly male (57%
and 53%, respectively), from singleton births (94% and
93%, respectively), white (95% of cases and siblings) and
privately insured (80% of cases) (table 1). The median
level of education was fifth grade for cases and fourth
grade for siblings, and median income for the year prior
to the child’s birth was US$85 000–US$100 000 (for cases
and siblings).
To date, the IPR Epidemiology Study includes 1010
participating households. For most of these households
(83%), all of their children enrolled in the IPR met inclu-
sion criteria for the Epidemiology Study subsample. Most
households (83%) include 1 or 2 children and some
(17%) include at least 3 children (online supplemental
table 1). Some of the households in the IPR Epidemiology
Study included a sibling (39%) and some included more
than one case (20%). Most household survey respondents
were partnered (married, remarried or living as married;
88%), employed (60%) and owned or are buying their
homes (87%) (online supplemental table 2). The median
reported annual household income for the year prior to
IPR enrolment was US$125 000–US$150 000. For most
households, the highest level of maternal and paternal
educations was bachelor’s degrees (37% and 35%, respec-
tively) or master’s degrees or professional degrees beyond
a bachelor’s (35% and 26%, respectively).
Neurologic, psychiatric and behavioural symptoms
Overall, the most common symptoms reported among
IPR Epidemiology Study participant cases were anxiety
(94%), emotional lability (92%) and obsessions (90%),
followed by somatic signs and symptoms (84%), irrita-
bility, aggression, severe oppositional behaviour (83%)
and sensory abnormalities (81%) (table 2). For nearly
all symptoms, 70%–80% of participants reportedly expe-
rienced an onset of that particular symptom that felt
‘abrupt and dramatic’. Nearly all participants (90%) were
affected by these symptoms before puberty. When asked if
these symptoms can be explained by a known neurologic
or medical disorder (such as Sydenham chorea, systemic
lupus erythematosus, Tourette disorder or others), very
few (n=39, 3%) replied affirmatively.
Symptom onset
Overall, slightly over half of cases reportedly had a ‘sudden
and dramatic’ nature of onset (58%) and just less than
half (42%) report ‘a gradual progression’ nature of their
symptom onset. Among those who reported a ‘sudden
and dramatic’ onset of symptoms, 54% also reported they
noticed early signs or symptoms in hindsight (table 3).
Among those who generally described their child’s
symptom onset as ‘a gradual progression’, 88% reported
a dramatic increase in symptoms occurred at some point
in time. ‘A gradual progression’ nature of onset or early
signs/symptoms noted in hindsight begin at 4 years of
age on average; a ‘sudden and dramatic’ nature of onset
or a subsequent dramatic increase in symptoms occurs
around 7 years of age on average. Most of those who
reported a ‘sudden and dramatic’ nature of onset quan-
tify the onset timing as within 1 week (62%), whereas only
26% of those who report a dramatic increase in symptoms
following ‘a gradual progression’ nature of onset estimate
Body- focused
repetitive
behaviours
(BFRB) (eg, hair
pulling, skin
picking, nail-
biting)
Any BFRBs 669 (57%)
Initial onset felt abrupt and dramatic 421 (63%)
Nail- biting disorder (onychophagia) 343 (51%)
Skin picking disorder (excoriation) 314 (47%)
Frequently chewing on the inside of the cheeks 129 (19%)
Hair pulling disorder (trichotillomania) 120 (18%)
Biting the lips until they bleed 112 (17%)
Severe restriction
of food intake
Any severe restriction of food intake 540 (46%)
Initial onset felt abrupt and dramatic 384 (71%)
Sensory issues (cannot stand the way food smells, feels, tastes, etc.) 404 (75%)
Restricted intake of specic foods 283 (52%)
Restricted intake of all food groups 240 (44%)
Observable weight loss 239 (44%)
Contamination fears 186 (34%)
Restricted uid intake and/or dehydration 151 (28%)
Fear of harm 113 (21%)
Obsession with body image or weight 97 (18%)
Unexpected
increase in food
intake
Any unexpected increase in food intake 270 (23%)
Initial onset felt abrupt and dramatic 169 (63%)
Selective mutism 189 (16%)
Table 2 Continued
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the time over which the dramatic increase occurs as within
1 week. Most of those who report the nature of onset as
‘sudden and dramatic’ or ‘a gradual progression’ recalled
a time when their child was symptom free (69% and 59%,
respectively).
We observed three main patterns in the parent reports
of initial symptom onset: (1) 27% reported sudden onset
with no report of any early signs and symptoms in hind-
sight, (2) 68% reported a (a) gradual onset with an even-
tual dramatic increase in symptoms (37%) or (b) sudden
onset with reported early signs and symptoms in hind-
sight (31%) or (3) 5% reported gradual onset without
ever experiencing a dramatic increase in symptoms.
These patterns will be the focus of subsequent analyses
of extant IPR Epidemiology Study data, including eval-
uating their potential association with phenotypic traits,
maternal health and other disease characteristics.
Suspected triggers
The leading suspected triggers for the initial onset of
PANS symptoms and subsequent flare episodes were
similar (online supplemental table 3). The most common
suspected trigger of flare episodes is infection or illness
(84%); approximately half of parents also point to
anxiety or stress (50%), environmental allergies (40%)
and being around someone who is strep positive (40%).
Among those who suspected the initial onset of PANS
symptoms was triggered by infection or illness (71%),
61% suspected the infection was strep throat.
Phenotypic traits and other characteristics
Table 4 describes various phenotypic traits and other
characteristics across cases and siblings. Many of these,
to our knowledge, have not been previously collected for
this patient population. Among cases, some of these are
reportedly more intense during a symptom flare.
Health conditions
Overall, 18% of cases and 7% of siblings reportedly have an
autoimmune or autoinflammatory condition other than
PANS/PANDAS (online supplemental table 4). Approx-
imately one- quarter (27%) of cases and 12% of siblings
have at least one food allergy diagnosed through formal
testing. Among them, the most common food allergies
were lactose intolerance/cow’s milk allergy (57% cases,
46% siblings), gluten intolerance/wheat allergy (55%
cases, 44% siblings) and eggs (32% cases, 29% siblings).
Most participants had received the most common vaccines
(online supplemental table 5). Approximately one- third
of cases (36%) and siblings (30%) have been vaccinated
according to a modified vaccine schedule.
Family health history
Among those with known and reported health of the
biological mother, 39% of participants’ biological
mothers have an autoimmune, autoinflammatory or
other immune- mediated condition. Most of the case
participants (90%, n=1060) reported a known health
history for their nuclear, biological family, including that
of the participant’s mother, father and siblings (online
supplemental table 6). The most common reported
conditions in the nuclear, biological family were allergies
(66%), mental illness (56%) and autoimmune condi-
tions (48%). Several participants had a brother (29%)
and/or sister (25%) with PANS and some had a mother
(15%) or father (9%) with a suspected PANS diagnosis.
On both the maternal and paternal sides of the family,
PANS/PANDAS were believed to be observed in cousins
(8%–10% and 4%–7%, respectively), aunts/uncles
(7%–8% and 3%–5%, respectively) and grandparents
(4%–5% and 2%–3%, respectively). Reports may be more
common on the maternal side.
Treatment and medication experience
1094 of the IPR Epidemiology Study sample had completed
the ‘treatment’ survey at the time of data analysis. The
treatments that have most commonly ever been tried in
Table 3 Nature of the onset of PANS feature by parent
report, n=1179
Nature of onset
‘Sudden and
dramatic’
(n=685, 58%)
‘A gradual
progression’
(n=494, 42%)
Ever symptom free 474 (69%) 290 (59%)
Noticed early signs and
symptoms (in hindsight)
Ye s 369 (54%)
No 316 (46%)
Age when rst noticed early/
rst signs (years), mean (SD)
4.1 (3.0),
N=369
4.0 (3.3)†
Dramatic increase in
symptoms at some point
Ye s 437 (88%)
No 57 (12%)
Age (years) at dramatic onset/
increase in symptoms, mean
(SD)
7.0 (3.6)* 7.2 (3.6),*
N=437
Duration of time over
which dramatic increase in
symptoms developed
<24 hours 141 (21%) 26 (6%)
24–72 hours 159 (23%) 41 (9%)
3 days to 1 week 120 (18%) 48 (11%)
1–3 weeks 138 (20%) 70 (16%)
3–6 weeks 53 (8%) 57 (13%)
6 weeks to 3 months 26 (4%) 74 (17%)
3–9 months 21 (3%) 72 (16%)
>9 months 20 (3%) 47 (11%)
Missing 7 2
*Missing n=2.
†Missing n=8.
PANS, paediatric acute- onset neuropsychiatric syndrome.
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Table 4 Phenotypic traits and other characteristics of cases and siblings by parent report, n=1781
Cases n=1179 Siblings n=602
Child has ever had or experienced the following:
Skin/tissue/muscle characteristics† Pallor (pale skin) 501 (44%)* 81 (15%)
Dandruff 299 (26%) 85 (16%)
Facial acne 335 (30%) 123 (23%)
Abnormal cysts on skin 63 (6%) 13 (2%)
Hypermobile, more exible than normal (in the elbows, knees,
ngers, etc)
303 (27%) 64 (12%)
Hyper- reexia (overactive or over- responsive reexes) 109 (10%)* 6 (1%)
Orofacial or tardive dyskinesias (involuntary repetitive
movements of the mouth and face)
249 (22%)** 4 (1%)
Dystonia (a movement disorder in which a person’s muscles
contract uncontrollably)
151 (13%)** 3 (1%)
Joint cracking 283 (25%) 55 (10%)
Subluxation, incomplete or partial dislocation of a joint 74 (7%) 16 (3%)
Non- genital warts 188 (17%) 46 (9%)
Flat feet 198 (17%) 41 (8%)
Itchy or crawling skin 303 (27%)** 35 (7%)
Thinning hair/hair loss 84 (7%)* 6 (1%)
Excessively long eyelashes 232 (20%) 61 (11%)
Dark circles under the eyes 630 (56%)** 79 (15%)
Keratosis pilaris (‘chicken skin’, small bumps on upper arms)‡ 366 (32%) 109 (20%)
Rashes‡ 332 (29%) 76 (14%)
Eczema‡ 316 (28%) 109 (20%)
Stretch marks (striae)‡ 182 (16%) 29 (5%)
Cradle Cap past the age of 3‡ 132 (12%) 31 (6%)
Café au lait spots‡ 99 (9%) 37 (7%)
Hypopigmented spots (white spots on the skin)‡ 81 (7%) 17 (3%)
Hyperpigmented spots (darkening of the skin)‡ 70 (6%) 11 (2%)
Psoriasis‡ 19 (2%) 6 (1%)
Pain- related characteristics† Muscle pain 529 (47%)** 61 (11%)
Joint pain 500 (44%)** 59 (11%)
Canker sores (inside the mouth) 342 (30%)* 72 (13%)
Cold sores (outside the mouth, on the lips) 99 (9%)* 20 (4%)
Reux/heartburn 293 (26%)* 63 (12%)
Headache 622 (55%)** 116 (22%)
Gastrointestinal (GI) disturbances 625 (55%)* 118 (22%)
Feeling of food getting caught in the throat 277 (24%)** 29 (5%)
Motion sickness 331 (29%)* 89 (17%)
Autonomic nervous system characteristics† Does not get fevers when sick 562 (50%) 25 (5%)
Fatigue 659 (58%)** 38 (7%)
Dizziness or vertigo 303 (27%)** 22 (4%)
Heat intolerance 448 (40%)* 35 (7%)
Cold intolerance 237 (21%)* 19 (4%)
Pupils dilate 647 (57%)** 13 (2%)
Excessive sweating 262 (23%)* 22 (4%)
Continued
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the study sample include antibiotics (88%), supplements
(81%) and oral non- steroidal anti- inflammatory drugs
(NSAIDs) (79%) (table 5). The treatments that were
most often reported as ever having at least partially alle-
viated symptoms in this study sample were the same: anti-
biotics (74%), NSAIDs (62%) and supplements (52%).
‘Tincture of time’/waiting it out was the approach most
reported as having made symptoms worse (42%) and the
only approach where worsening of symptoms was more
commonly reported than alleviation.
Disease impact, experience and healthcare utilisation
Parents consistently reported a high degree of disease-
related disruption in their child’s lives (9.0±1.5 on a
Cases n=1179 Siblings n=602
Miscellaneous characteristics† Crust behind the ears 162 (14%) 42 (8%)
Redness/hotness of ears 309 (27%)* 45 (8%)
Excessive ear wax 290 (26%) 77 (14%)
Swelling/puffy face 146 (13%)** 12 (2%)
Frequent nose bleeds 212 (19%) 49 (9%)
Needs to stand on head 148 (13%)** 12 (2%)
Any seizures 91 (8%)* 10 (2%)
Sinus issues 391 (35%)* 68 (13%)
Other traits and characteristics:
Skin tone Light 917 (78%) 456 (76%)
Medium 249 (21%) 138 (23%)
Dark 13 (1%) 7 (1%)
Missing 0 1 (<1%)
Eye colour (may select multiple responses) Brown 422 (36%) 226 (38%)
Hazel 222 (19%) 84 (14%)
Green 100 (8%) 50 (8%)
Blue 487 (41%) 259 (43%)
Hair colour Black 55 (5%) 25 (4%)
Brown 732 (62%) 353 (59%)
Red 49 (4%) 26 (4%)
Blonde 343 (29%) 198 (33%)
Any white or silver hair (not including
platinum blonde)
Yes 75 (6%) 20 (3%)
Hair texture (thickness of individual strands
of hair)
Fine 324 (27%) 192 (32%)
Medium 579 (49%) 277 (46%)
Coarse/thick 276 (23%) 133 (22%)
Hair thickness (density of the hair follicles
across the scalp)
Thick 497 (42%) 212 (35%)
Medium 554 (47%) 310 (52%)
Thin 128 (11%) 80 (13%)
Child is/has been a competitive gymnast,
gure skater or dancer†
Yes 92 (8%) 31 (6%)
Dominant hand† Left 124 (11%) 64 (12%)
Right 952 (84%) 457 (85%)
Ambidextrous 57 (5%) 17 (3%)
Considers child to be exceptionally gifted
(cases, please answer this question for
your child prior to the onset of symptoms)
Yes 388 (34%) 125 (23%)
Any adverse reaction to insect stings/bites§ Yes 721 (69%) 304 (57%)
*50%–75%, ** >75% report the characteristic is more intense during a are episode.
†Among n=1133 cases/n=538 siblings; by parent report, for cases, these included hyperlexia, hypercalculia, hyperthymesia, photographic memory
(8%) and/or other.
‡Did not ask/report whether characteristic/trait intensied during a are episode.
§Among n=1051 cases/n=536 siblings who have experienced an insect sting/bite.
Table 4 Continued
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10- point scale) and a high degree of severity (7.9±1.9
on a 10- point scale) (online supplemental table 7).
Approximately a quarter of cases had been hospitalised
for disease- related reasons and 60% had their ability to
attend school compromised in some way due to PANS
(39% had stopped attending school for at least a month
at some point). Most cases were receiving special accom-
modations in school, mostly individualised education
programmes, 504 plans, home- bound home schooling
and help from a resource teacher.
Most participants reported having difficulty locating
(84%) and accessing (87%) appropriate care and treat-
ment (online supplemental table 8). The primary barriers
to access they reported were a shortage of specialty providers
and treatment services where they live as well as cost and
or a lack of insurance coverage. Most participants (64%)
waited more than a month for a new patient appointment
with the first specialist they saw with their child. Overall,
patients had seen an average of five providers (SD: 5.2)
seeking treatment and management of PANS symptoms.
Participants reported that, on average, less than half
(46%, SD: 37%) of their PANS- related care and treatment
costs in the past year were covered by insurance and/or
other healthcare coverage. Overall, participants spent
an estimated US$5447 (SD: US$9698) out of pocket on
PANS- related care in the prior year and report an esti-
mated US$11 177 (SD: US$22 665) as the most spent out
of pocket on PANS- related care in any 1 year.
Interest in sharing existing data and making additional data
contributions
Most participating households (83%) provided permis-
sion for their deidentified data to be shared with any
third party that the PRAI, the IPR sponsor, recommends.
Another 12% were more selective, but still provided
permission for their deidentified data to be shared with
specific third parties. Nearly all of them (93%) gave
permission for their data to be shared specifically with
physicians and scientists/researchers. Overall, 94% of
the IPR Epidemiology Study households are interested
in sharing their data with physicians and scientists/
researchers.
Additionally, 84% of all IPR Epidemiology participants
are interested in sharing biological samples and/or spec-
imens from their child. Most would be willing to consider
sharing any sample or specimen type, but participants
seemed most receptive to sharing saliva, hair, fingernails
and/or urine. Similarly, overall, 75% of participants
reported a willingness to share a complete set of their
child(ren)’s deidentified medical records, though only
about 17% had already obtained the records and were
ready to share them at the time of the survey. Case and
sibling participants were similar in their willingness to
share specimens and medical records.
In summary, this paper provides an overview of the base-
line data we collected from participants in the IPR Epide-
miology Study between July 2020 and December 2021.
Enrolment is open and ongoing and, to this end, the IPR
invites families affected by these conditions to enrol and
dramatically expand our sample size (www.pansregistry.
org). The IPR provides researchers with detailed pheno-
typic information from thousands of individuals and fami-
lies affected by PANS and related conditions to accelerate
clinical research and identify the causes of these condi-
tions. We invite external research collaborators to use
Table 5 Treatment experience overview, n=1094 cases
Type Treatment Ever tried
Among those who ever tried….
Has at least partially
alleviated symptoms
Ever made
symptoms worse
Antimicrobial Antibiotics 959 (88%) 812 (85%) 174 (18%)
Antifungals 336 (31%) 205 (61%) 53 (16%)
Antivirals 280 (26%) 156 (56%) 25 (9%)
Immunomodulatory Oral non- steroidal anti- inammatory drugs 869 (79%) 673 (77%) 23 (3%)
Corticosteroids 503 (46%) 346 (69%) 176 (35%)
Intravenous Immunoglobulin (IVIG) 275 (25%) 224 (81%) 80 (29%)
Monoclonal antibody therapy (eg, rituximab) 46 (4%) 40 (87%) 11 (24%)
Plasmapheresis 35 (3%) 30 (86%) 5 (14%)
Subcutaneous Immunoglobulin (SCIg) 22 (2%) 9 (41%) 9 (41%)
Psychotherapy Psychotropic medications (including selective serotonin
reuptake inhibitors)
519 (47%) 275 (53%) 251 (48%)
Cognitive–behavioural therapy 491 (45%) 218 (44%) 80 (16%)
Other Supplements 886 (81%) 566 (64%) 172 (19%)
‘Tincture of time’ (wait it out) 704 (64%) 134 (19%) 455 (65%)
Diet modication 681 (62%) 431 (63%) 40 (6%)
Antihistamines (H1 and H2 blockers) 631 (58%) 389 (62%) 72 (11%)
Homeopathy 463 (42%) 302 (65%) 82 (18%)
Tonsillectomy 340 (31%) 194 (57%) 37 (11%)
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the IPR database for analyses and ancillary study recruit-
ment. This cohort provides a previously absent opportu-
nity to conduct analyses that address unresolved research
questions, including further investigation of the possible
involvement of immune dysregulation in the disease
processes affecting their enrolled child(ren).
Strengths and limitations
This study is unique because the participant sample is
selected from the IPR, the first large- scale, centralised
epidemiologic registry in the world designed to accelerate
research on the broad spectrum of PANS. The IPR Epide-
miology Study was designed to be dynamic and flexible,
to longitudinally follow participants, facilitate ancillary
study recruitment based on detailed selection criteria and
expand the scope of the database (eg, integrate medical
record information, biospecimens). The Study has also
been set up to enrol and prospectively track healthy
siblings who may develop PANS symptoms in the future.
It is important to note that the study investigators recog-
nise that siblings of self- reported PANS cases should not
be considered study controls. We will keep detailed docu-
mentation of the data collected over time and monitor
our success at tracking participants over time, comparing
their baseline characteristics to those we lose to follow- up.
Participation in the IPR Epidemiology Study is not
restricted to those who meet the current working criteria
for PANS.11 While current recommendations for eval-
uating suspected PANS cases include a comprehensive
medical and psychiatric history, a thorough physical
exam, and an overall evaluation by a treating physician,3
this approach limits the potential for conducting large-
scale studies as it is challenging to pool large sample
sizes and to standardise and centralise this type of data.
While many study participants report PANS- like features
but likely do not meet the full set of current working
criteria for the condition, the strength of the IPR Epide-
miology Study is that it includes thousands of participants
with related conditions. Furthermore, the IPR Epide-
miology Study enables study of the broad spectrum of
PANS- like conditions and application of more restric-
tive selection criteria within the study sample to meet
specific research selection criteria. It is important to note
that the survey data we have presented here is based on
parental self- report and subject to recall bias, particularly
when reporting clinical information that has not been
recorded in writing and/or recalling events that occurred
in the distant past. To date, the IPR Epidemiology Study
includes a convenient sample of participants that is not
generalisable nor representative of any region, demo-
graphic, nor specific patient population. Furthermore,
the IPR Epidemiology study sample is subject to selection
bias related to our recruitment approach and the status
of PANS within the US medical system. It is possible that
those included represent, on average, parents who are
the most motivated to further solidify PANS as a diagnosis
and to accelerate research that will lead to better treat-
ment for their children.
Although we asked participants to report any codi-
agnosis with neurological, developmental and other
conditions for cases and siblings, the response field
was open text and we do not believe we collected
consistent and complete replies. In the first follow- up
survey, we have included a multiple- choice list of
codiagnoses as well as a list of known infections that
preceded a flare episode (for cases only) to better
ascertain these characteristics and experiences.
Future plans include increasing sample size,
collecting longitudinal survey data, recruiting appro-
priate study controls and expanding the scope of the
database, prioritising medical record data integration
and creating a linked biobank. Secondary analyses of
extant data will prioritise identifying subgroups by
phenotypic traits, maternal health and characteristics
of disease onset.
Acknowledgements The authors thank the participating families for their
dedicated time and commitment to their community goal of building the IPR. We
appreciate the input of those who helped inform our survey design, the time of
those who shared their children’s health information and the many contributions of
those who supported the fundraising effort to support this project. We would like
to acknowledge the support of Dacima Software, the survey platform on which the
rst wave of data reported here was collected. We thank Dr Herb Lachman for his
guidance and critical review of this manuscript.
Contributors EM and JG jointly conceptualised the IPR. EM designed the
epidemiological study, acquired ethics approvals, analysed the data, led the writing
of the original draft of this manuscript and is responsible for the overall content
as guarantor. JG contributed to creating the surveys and was responsible for
acquisition of funding, study participant recruitment and contributed to reviewing
and editing this manuscript. Both authors have read and approve of this nal
version of the manuscript for publication.
Funding This study was funded by the Pediatric Research & Advocacy Initiative
(PRAI; https://praikids.org/), a 501c3 non- prot organisation founded by the patient
community.
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the
design, or conduct, or reporting, or dissemination plans of this research. Refer to
the Introduction section for further details.
Patient consent for publication Not applicable.
Ethics approval This study involves human participants but IntegReview (now
Avarra) institutional review board (#PRAI_svy001) exempted this study. Participants
gave informed consent to participate in the study before taking part.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. This
publication contains a description of data collected by the International PANS
Registry (IPR). The IPR team is committed to data sharing. Deidentied data from
the IPR are available to the public via an online data request portal and subject to an
approval process (https://pansregistry.org/researchers/). Complete data dictionaries
describing the survey data available may also be found at this site. The registry is
also intended to serve as a recruitment tool for new studies. Please contact the study
PI and lead author of this manuscript to further discuss interest ( emaster@ uw. edu).
Informed consent documents may be made available upon request. Participants
who provided their email address upon enrolment consented to be contacted in the
future with messages/updates and subsequent data collection requests from the
IPR and, potentially, other researchers who would like to select a study sample from
the IPR recruitment pool. The data they provided when they enrolled in the IPR may
be used for future studies and recruitment purposes (ie, study inclusion criteria).
We allow participants to select specic permissions for the type of third party with
whom they wish their data would be shared with when they enrol and will select
data accordingly for outside requests. Participant data is kept condential. The data
is coded with a non- identifying subject ID and the le with identifying information is
kept on a secure, password- protected server.
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Supplemental material This content has been supplied by the author(s). It has
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
peer- reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non- commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non- commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iD
Erin EMasterson http://orcid.org/0000-0002-1354-7641
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... The described disorders are accompanied by somatic symptoms and motor abnormalities. Common abnormalities include sleep disturbance -waking up from sleep, difficulty falling asleep, night terrors, and urinary system symptoms without signs of infection -urinary urgency, urinary frequency, nocturnal enuresis [20]. The most common motor abnormalities, however, are tics. ...
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PANDAS (Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) and PANS (Paediatric Acute-onset Neuropsychiatric Syndrome) are rare diseases and there is scant information about diagnostic and treatment options. The aim of this study is to summarise the current state of knowledge about the diseases. Articles from the PubMed database were sought and articles found dealing with the diseases were summarised and the knowledge assessed. The etiology of PANDAS and PANS syndromes has not yet been defined. There are hypotheses assuming that streptococcal infection can trigger an immune response that results in prominent neuropsychiatric symptoms. Diagnostic criteria focus on a clinical picture that includes the sudden onset of tics, obsessivecompulsive behaviour, anxiety and mood disorders following infection. Therapy for PANDAS and PANS syndromes is based at present on a number of therapeutic avenues for selecting the best plan. Immunomodulatory therapies, such as plasmapheresis and immunoglobulin administration, are being explored as methods to reduce the severity of the intractable symptoms in children. In addition, behavioural and pharmacological therapies, such as antipsychotics or anticonvulsants, are being used to manage symptoms. Despite the clear interest in understanding these syndromes, there is a need for further research, especially in the area of identifying pathomechanisms and optimal treatment strategies. Improving diagnostic and therapeutic processes will ensure faster recovery and prevention of these conditions in paediatric patients in the interest of their well-being and comfort.
... Additionally, cross-sectional prevalence data show that approximately one-third of patients meeting PANS criteria eventually develop enthesitis-related arthritis (ERA) and/or inflammatory back pain, further supporting a role for inflammation in this disorder [18,24]. Furthermore, inflammatory/autoimmune disorders are prevalent in first-degree family members[8, 25,26]. However, the direct effects of PANSassociated serum antibodies on the brain have not been determined. ...
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Acute onset of severe psychiatric symptoms or regression may occur in children with premorbid neurodevelopmental disorders, although typically developing children can also be affected. Infections or other stressors are likely triggers. The underlying causes are unclear, but a current hypothesis suggests the convergence of genes that influence neuronal and immunological function. We previously identified 11 genes in Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS), in which two classes of genes related to either synaptic function or the immune system were found. Among the latter, three affect the DNA damage response (DDR): PPM1D, CHK2, and RAG1. We now report an additional 17 cases with mutations in PPM1D and other DDR genes in patients with acute onset of psychiatric symptoms and/or regression that their clinicians classified as PANS or another inflammatory brain condition. The genes include clusters affecting p53 DNA repair (PPM1D, ATM, ATR, 53BP1, and RMRP), and the Fanconi Anemia Complex (FANCE, SLX4/FANCP, FANCA, FANCI, and FANCC). We hypothesize that defects in DNA repair genes, in the context of infection or other stressors, could contribute to decompensated states through an increase in genomic instability with a concomitant accumulation of cytosolic DNA in immune cells triggering DNA sensors, such as cGAS-STING and AIM2 inflammasomes, as well as central deficits on neuroplasticity. In addition, increased senescence and defective apoptosis affecting immunological responses could be playing a role. These compelling preliminary findings motivate further genetic and functional characterization as the downstream impact of DDR deficits may point to novel treatment strategies.
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This article examines the degree to which major domains of child development are affected by Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)/Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). Using cross-sectional survey data collected with an international sample of parents who identify as having children with PANS/PANDAS (N = 402), this study analyzed parent-reported developmental impacts and access to treatment and adequate supports. Parents reported that PANS/PANDAS negatively impacted their children’s development across all domains: Emotional Development (92% of children), Social Development (90%), Cognitive Development (86%), Academic Growth (86%), Identity Development (83%), Talent Development (73%) and Language Development (50%). In addition, developmental impacts were likely to be more severe for children whose parents reported a greater number of inadequate supports with parenting, school, extracurricular activities, and crisis situations. These results indicate that children and families affected by PANS/PANDAS need better support to maximize children’s opportunities, at home, in school, and in their communities, to continue developing despite challenging neuropsychiatric symptoms.
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Background: There are presently very few genetic studies for PANS (Pediatric Acute-Onset Neuropsychiatric Syndrome) or PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections). More work in genetic associations for PANS and PANDAS (P/P) is needed to increase understanding of these debilitating childhood disorders that have a range of presentations. Objective: This work represents a novel approach that aims to determine genetic associations between P/P and other diseases, disorders and traits (hereafter referred to as phenotypes). Methods: Consumer genetic data (23andMe, AncestryDNA) for 155 patients with P/P were obtained from consenting parents over a period from 2018 to 2020. An analysis plan for this work was registered at Open Science Framework, additional genotypes imputed using Impute.me, and polygenic risk scores for 1,702 phenotypes calculated for each of the 155 P/P patients. Results: One-sample t-tests performed across the 155 individual risk scores revealed that P/P is statistically significantly associated with 21 different groups of Single Nucleotide Polymorphisms (SNPs) that are in turn associated with 21 phenotypes. Some of the 21 phenotypes (see Table 3) are previously known to be related to or associated with P/P: a group of SNPs associated with Tourette’s Syndrome, and another group associated with Autism Spectrum Disorder or Schizophrenia, and a third associated with “feeling nervous” yielded t-tests with p values of 1.2x10-5, 1.2x10-11 and 1.0x10-5 respectively for association with the P/P data. This validated our analysis methodology. Our analysis also revealed novel genetic associations such as between P/P and plasma anti-thyroglobulin levels (p=1.3x10-7), between P/P and triglycerides (p=5.6x10-6), and between P/P and Lewy body disease (p=7.8x10-6), inviting further investigation into the underlying etiology of P/P. Conclusion: P/P is associated with many phenotypes not previously recognized as being connected to P/P. Further work on these connections can lead to better understanding of P/P.
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Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are clinical conditions characterized by the sudden onset of obsessive–compulsive disorder and/or tics, often accompanied by other behavioral symptoms in a group of children with streptococcal infection. PANDAS-related disorders, including pediatric acute-onset neuropsychiatric syndrome (PANS), childhood acute neuropsychiatric symptoms (CANS), and pediatric infection triggered autoimmune neuropsychiatric disorders (PITANDs), have also been described. Since first defined in 1998, PANDAS has been considered a controversial diagnosis. A comprehensive review of the literature was performed on PubMed and Scopus databases, searching for diagnostic criteria and diagnostic procedures of PANDAS and related disorders. We propose a test panel to support clinicians in the workout of PANDAS/PANS patients establishing an appropriate treatment. However, further studies are needed to improve our knowledge on these acute-onset neuropsychiatric conditions.
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Pediatric acute onset neuropsychiatric syndrome (PANS) is viewed as an autoimmune/autoinflammatory condition characterized by the abrupt onset of severe neurological and psychiatric symptoms, in particular obsessive-compulsive disorder (OCD), tics, anxiety, mood swings, irritability, and restricted eating, often triggered by infections. However, direct evidence of autoimmunity, infections, or a proinflammatory state is often lacking, and there is no unifying pathogenic pathway. This could be due to underlying genetic heterogeneity, which could lead to the development of PANS through different cellular and molecular pathways. Unfortunately, little is known about the genetic basis of PANS. Consequently, we carried out whole exome sequencing (WES) on a U.S. cohort of 386 cases who met diagnostic criteria for PANS, including 133 family triads, and whole genome sequencing (WGS) on ten cases from the European Union, who were selected for WGS because of severe PANS symptoms. We focused on identifying potentially deleterious genetic variants that were either de novo or ultra-rare with a minor allele frequency (MAF) < 0.001. Candidate mutations were found in 11 genes: PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1 in a total of 20 cases, which included two sets of siblings, and two or more unrelated subjects with ultra-rare variants in SGCE, NLRC4, RAG1, and SHANK3. The PANS candidate genes we identified separate into two broad functional categories. One group regulates peripheral innate and adaptive immune responses (e.g., PPM1D, CHK2, NLRC4, RAG1, PLCG2), some of which also influence microglia function. Another is expressed primarily at neuronal synapses or directly modulates synaptic function (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). These neuronal PANS candidate genes are often mutated in autism spectrum disorder, developmental disorders, and myoclonus-dystonia. In fact, eight out of 20 cases in this study developed PANS superimposed on a preexisting neurodevelopmental disorder. There is, however, clinical overlap between these two groups and some crossover expression (e.g., some neuronal genes are expressed in immune cells and vice versa) that diminishes the neuronal/immune dichotomy. Genes in both categories are also highly expressed in the enteric nervous system, and in the choroid plexus and brain vasculature, suggesting they might contribute to a breach in the blood-CSF barrier and blood-brain barrier (BBB) that would permit the entry of autoantibodies, inflammatory cytokines, chemokines, prostaglandins, and autoantibodies into the brain. Thus, PANS is a genetically heterogeneous condition that can occur as a stand-alone neuropsychiatric condition or co-morbid with neurodevelopmental disorders, with candidate genes functioning at several levels of the neuroinflammatory axis.
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Little is known about the long-term prognosis of children with pediatric acute-onset neuropsychiatric syndrome (PANS). Out of the 46 eligible patients from the Karolinska PANS cohort, 34 consented to participate in a follow-up (median 3.3 years). Participants underwent a thorough clinical evaluation and were classified according to their clinical course. Resulting groups were compared on clinical characteristics and laboratory test results. We observed significant reductions in clinician-rated PANS symptom severity and improved general function. Two patients were classified as remitted, 20 as relapsing-remitting, and 12 as having a chronic-static/progressive course. The latter group had an earlier onset, greater impairment and received more pharmacological and psychological treatments. Although remission was rare, the majority of children with PANS were significantly improved over the follow-up period but a non-negligible minority of patients displayed a chronic-static/progressive course and required additional treatments. The proposed definitions of flare and clinical course may be useful in future clinical trials.
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Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a descriptive clinical entity defined by the abrupt onset of psychiatric and somatic symptoms leading to significant loss of function. Data on well-characterized PANS patients are limited, biomarkers have yet to be identified, and a solid evidence base to guide treatment is lacking. In this study, we present our experience of a systematic evaluation of the first 45 patients included in a Swedish cohort. Methods: During the period 2014-2018, our clinic received 100 referrals regarding suspected PANS. All patients underwent a standardized psychiatric/medical evaluation by a child/adolescent psychiatrist and a clinical psychologist or a nurse. Those with severe symptoms were also assessed by a pediatric neurologist and a pediatric rheumatologist. Laboratory tests were obtained at different time points in an attempt to capture an active disease state. Results: Of the 100 referrals, 45 met strict PANS criteria and consented to participate in a long-term follow-up study. The median age at intake was 7.2 years (range 3.0-13.1) and 56% were male. Ninety-three percent fulfilled both criteria for acute/atypical onset of PANS symptoms and having had an infection in relation to onset. Sixteen percent had an onset of an autoimmune or inflammatory disorder in temporal relation to the onset of PANS-related symptoms. The most common onset symptoms were obsessive-compulsive disorder (89%), anxiety (78%), and emotional lability (71%). Twenty-four percent had a preexisting autoimmune disease (AD) and 18% a preexisting psychiatric/neuropsychiatric diagnosis. Sixty-four percent of biological relatives had at least one psychiatric disorder and 76% at least one AD or inflammatory disorder. Complement activation (37%), leukopenia (20%), positive antinuclear antibodies (17%), and elevated thyroid antibodies (11%) were the most common laboratory findings. Conclusions: In our PANS cohort, there was a strong indication of an association with AD. Further work is needed to establish whether any of the potential biomarkers identified will be clinically useful. Long-term follow-up of these patients using the Swedish national registers will enable a deeper understanding of the course of this patient group.
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The association between obsessive–compulsive disorder (OCD) and Tourette’s/chronic tic disorders (TD/CTD) with autoimmune diseases (ADs) is uncertain. In this nationwide study, we sought to clarify the patterns of comorbidity and familial clustering of a broad range of ADs in individuals with OCD, individuals with TD/CTD and their biological relatives. From a birth cohort of 7 465 455 individuals born in Sweden between 1940 and 2007, we identified 30 082 OCD and 7279 TD/CTD cases in the National Patient Register and followed them up to 31 December 2013. The risk of 40 ADs was evaluated in individuals with OCD, individuals with TD/CTD and their first- (siblings, mothers, fathers), second- (half siblings) and third-degree (cousins) relatives, compared with population controls. Individuals with OCD and TD/CTD had increased comorbidity with any AD (43% and 36%, respectively) and many individual ADs. The risk of any AD and several individual ADs was consistently higher among first-degree relatives than among second- and third-degree relatives of OCD and TD/CTD probands. The risk of ADs was very similar in mothers, fathers and siblings of OCD probands, whereas it tended to be higher in mothers and fathers of TD/CTD probands (compared with siblings). The results suggest a familial link between ADs in general (that is, not limited to Streptococcus-related conditions) and both OCD and TD/CTD. Additional mother-specific factors, such as the placental transmission of antibodies, cannot be fully ruled out, particularly in TD/CTD.
Article
Background: Paediatric acute-onset neuropsychiatric syndrome (PANS) is a newly defined symptom-based condition that mainly occurs in children and adolescents. Few studies have described the clinical characteristics of the syndrome. Methods: We clinically assessed and reviewed the medical histories of children and adolescents (aged 4-14 years) with suspected PANS who were referred to a specialist clinic in Gothenburg, Sweden, by local paediatricians and child psychiatrists. We scored severity of symptoms and impairment retrospectively for the timepoint with the most severe symptoms using the PANS scale. Findings: Of 41 patients (37 referred and four visited upon parents' request), 23 (ten girls and 13 boys) met PANS diagnostic criteria. Mean age at PANS onset was 8·5 years (SD 3·37). 11 (48%) patients had a family history of developmental or neuropsychiatric disorders in a first-degree relative and 11 (48%) had a family history of autoimmune or inflammatory diseases in a first-degree relative. 17 (74%) patients had been previously diagnosed with a developmental disorder (n=5) or had symptoms indicative of developmental problems (n=12). A verified or suspected infection was temporally related to PANS onset in all patients; the infection was bacterial in ten (43%) patients (eight had streptococcal infection and two an infection caused by other bacteria) and viral in 13 (57%) patients. All patients had a relapsing-remitting course of illness. The mean PANS scale symptom score was 46 (SD 3·67) and the mean impairment score was 45 (2·74). Antibiotic treatment was reported as beneficial by the parents of 12 (63%) of the 19 children who received antibiotics. Interpretation: Our PANS cohort had severe, acute-onset, complex neuropsychiatric symptoms, a relapsing-remitting symptom course, and possible infectious triggers. Further research into the cause of, and appropriate treatment for, PANS is warranted. Funding: Swedish Brain Foundation.