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Paediatric acute-onset neuropsychiatric syndrome in children and adolescents: an observational cohort study
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Paediatric acute-onset neuropsychiatric syndrome in children and adolescents: an observational cohort study Mats Johnson, Elisabeth Fernell, Iulian Preda, Lena Wallin, Anders Fasth, Carina Gillberg, Christopher Gillberg
Summary
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.
Lancet Child Adolesc Health 2019 Published Online January 28, 2019 http://dx.doi.org/10.1016/ S2352-4642(18)30404-8 See Online/Comment http://dx.doi.org/10.1016/ S2352-4642(19)30021-5 Gillberg Neuropsychiatry Centre (M Johnson MD, Prof E Fernell MD, L Wallin MD, Ca Gillberg MD, Prof Ch Gillberg MD) and Department of Paediatrics, Institute of Clinical Sciences (I Preda MD, Prof A Fasth MD), Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden Correspondence to: Dr Mats Johnson, Gillberg Neuropsychiatry Centre, Sahlgrenska Academy, Gothenburg University, 411 19 Gothenburg, Sweden [email protected]
Funding Swedish Brain Foundation. Copyright © 2019 Elsevier Ltd. All rights reserved.
Introduction Paediatric acute-onset neuropsychiatric syndrome (PANS) is characterised by abrupt onset of a broad range of neuropsychiatric symptoms.1 PANS has increasingly replaced the term paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)2 to focus entirely on symptoms, given that several infectious agents other than streptococci, as well as mechanisms other than infection, might be involved in the disorder. PANDAS is specifically linked to streptococcal infections and now considered to be a subgroup of PANS. Diagnosis of PANS is done by exclusion;1,3–7 it is diagnosed only when symptoms are not better explained by a known neurological, medical, or psychiatric disorder.1,6 Criteria for PANS, and guidelines for its assessment and treatment, have been published by the PANS Research Consortium.1,3–7 According to this definition, PANS onset is acute and dramatic, and includes obsessive-compulsive disorder (OCD) or eating restriction, and at least two other coinciding symptoms (panel). PANS has been linked to several different disease mechanisms, including neurological, endocrine, and metabolic processes, and post-infectious autoimmune
and neuroinflammatory disorders.1,3,8 In a case series of five patients, Frankovich and colleagues9 described five different infectious or autoimmune causes of the syndrome. Neuroinflammation is postulated to have a part in the initiation and progression of symptoms in most patients, with some case series documenting immune abnormalities in more than 80% of patients.10,11 However, in many patients, the definite cause cannot be identified by clinical investigations, laboratory tests, or cerebral imaging. Macerollo and Martino12 argued that the evidence for a post-infectious, immune-mediated patho physiology is insufficient and that larger, prospective studies are needed to reshape the nosography of PANS and identify the underlying mechanisms of the condition. Similarly, a report7 by the PANS Research Consortium stated that additional research is needed to understand the clinical heterogeneity of the condition. Treatment of PANS includes antimicrobial inter ventions and immunomodulatory or anti-inflammatory therapies that are given alongside supportive inter ventions (eg, family and school support), psychoactive medications, and cognitive behavioural therapy.6 These treatments have been reported to reduce or eliminate
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Research in context Evidence before this study Paediatric acute-onset neuropsychiatric syndrome (PANS) is a recently described clinical condition defined by acute onset of a broad spectrum of neuropsychiatric symptoms. Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is considered to be a subgroup of PANS. Proposed triggers of PANS are infections and inflammatory and autoimmune reactions. Using the search terms “PANS” and “PANDAS”, we searched PubMed without language restrictions up to Nov 1, 2018, for articles related to these conditions. We found few detailed descriptions of clinical cohorts, which were mainly from North America. We also found reviews of studies of treatments for PANS, which reported variable and inconclusive results. Added value of this study This study is among the first to describe a cohort of patients with PANS from a European country. The symptom profiles of
For the PANS scale see http://www.nepans.org/ uploads/8/1/4/0/81404234/ pandas_pans_scale.pdf
symptoms,4–7,13 but are ineffective in some patients, with some having ongoing symptoms that require continuous intervention and support.7 Initial treatment with antibiotics is recommended by the PANS Research Consortium for all patients with PANS, including those without documented infections. This recommendation is supported by extensive clinical experience from a large number of patients of PANS symptom improve ment with antibiotics, including reports of patients who have had complete and lasting remission of symptoms during antibiotic treatment.4,6,11 However, in a 2018 systematic review of available case reports and trials, Sigra and colleagues14 concluded that the evidence for using antibiotics is inconclusive. Similarly, Swedish national guidelines, published by the National Board of Health and Welfare in 2017,15 concluded that the scientific evidence for the treatment of PANS is insufficient. Evaluation of treatment might also be complicated by the fact that patients can have a relapsing–remitting, chronic–static, or chronic–pro gressive course of illness. The aim of this study was to report data from a group of children and adolescents with suspected PANS who were referred to a specialist centre in Sweden for clinical evaluation, and to compare the symptom profiles and trajectories of these patients with those of pre viously described cohorts, mainly from North America.
Methods
Study participants Patients were children and adolescents (aged 4–14 years), mostly from the southwestern part of Sweden, who were referred to the Child Neuropsychiatry Clinic, associated with the Gillberg Neuropsychiatry Centre, Gothenburg, 2
our patients, who were from Sweden, were similar to those described for North American cohorts and included acute onset of psychiatric and neurological symptoms, regression in cognitive and motor abilities, a relapsing–remitting symptom course, with periods of relapse related to infections, and periodically severe impairments in daily life. In all patients, onset of PANS occurred after a bacterial or viral infection, and many parents reported that their children had responded well to antibiotic treatment, with long periods of partial or complete remission of symptoms. Implications of all the available evidence Our findings are consistent with previous observations of distinct symptom profiles and trajectories for patients with PANS and support a post-infectious mechanism for the condition and possible beneficial effects of antibiotic treatment.
Sweden, between Feb 1, 2015, and Dec 31, 2017, by their local paediatrician or child psychiatrist. The study was approved by the local ethical review board. All parents and participants provided informed consent after receiving a complete description of the study.
Procedures Parents were interviewed in a semi-structured manner about family histories of developmental or neuro psychiatric disorders (eg, attention deficit hyperactivity disorder [ADHD], autism spectrum disorder, OCD, anorexia, depression, anxiety, or learning difficulties) and autoimmune or inflammatory disorders, the child’s early development, previous assessments, and medical and psychiatric histories. We also collected information about the timing and nature of the symptoms that led to suspicion of PANS; potential triggers, such as infections; and previous treatments. Previous medical records were reviewed. All patients were assessed by EF and MJ at a clinical visit. Severity of symptoms and impairment was rated by the investigators during interviews with parents and patients using the PANS scale, which was developed by Swedo, Leckman, and colleagues (National Institute of Mental Health [NIMH], personal communication). On the scale, each symptom included in the PANS criteria is scored from 0 to 5 points (none to very severe), with a total score range of 0–50 points. The impairment part of the scale estimates impairment in self-esteem, family life, social acceptance, and school or job functioning, with a total score range of 0–50 points (none to extreme difficulties). Onset of PANS had occurred several months or years before the study in many patients, and symptom ratings for the most severe period were made retro spectively. Parents of children who had received antibiotics
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were asked for their global impression of treatment response.
Statistical analysis We used descriptive statistics to summarise quantitative data and calculated means and SDs for PANS scale symptom and impairment scores.
Role of the funding source The funder of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results 37 patients were referred to the Child Neuropsychiatry Clinic between Feb 1, 2015, and Dec 31, 2017, by their local paediatrician, paediatric neurologist, or child psychiatrist, and four were included after their parents contacted the clinic following their child’s assessment by a local paediatrician or child psychiatrist. Of these, 23 patients (13 boys and ten girls), with a mean age at PANS onset of 8·5 years (SD 3·37; range 3–14), met diagnostic criteria for PANS (panel).1 18 children did not meet PANS criteria—for example, they did not have typical acute onset with complex symptoms or had other neurological or neuropsychiatric symptoms, such as regressive autism, epilepsy, or other identified neuro logical or neuro psychiatric disorders. Seven of these children had acute, post-infectious onset with symptoms such as irritability, anxiety, regression, motor or sensory abnormalities, tics, and fatigue, but did not have the obsessive-compulsive component necessary for PANS diagnosis. 11 children had a family history of developmental or neuropsychiatric disorders in a first-degree relative and 11 had a family history of autoimmune or inflammatory diseases in a first-degree relative (table 1). For two children, autoimmune or inflammatory disorders were described in more than one first-degree relative (ie, one child had two family members with ulcerative colitis, and the other had one family member with hypothyroidism and one with type 1 diabetes), whereas nine children had one family member with an autoimmune or inflammatory disorder (including coeliac disease, psoriasis, Crohn’s disease, Guillain-Barré syndrome, multiple sclerosis, rheumatoid disorder, type 1 diabetes, IgA vasculitis [also known as Henoch-Schönlein purpura], or thyroid disorder). In ten children, PANS onset was preceded (within 4 weeks) by a suspected (n=2) or verified (n=6) streptococcal infection or by an infection caused by a non-streptococcal bacterium (n=2; including an upper respiratory infection in one child and otitis media in the other; table 1). 13 children had a suspected viral infection before onset of PANS (table 1); the timing of this infection, as related to PANS onset, was within 4 weeks
Panel: Diagnostic criteria for paediatric acute-onset neuropsychiatric syndrome (PANS)1 Criterion 1 Abrupt, dramatic onset of obsessive-compulsive disorder or severely restricted food intake. Criterion 2 Concurrent presence of additional neuropsychiatric symptoms, with similarly severe and acute onset, from at least two of the following seven categories: anxiety; emotional lability or depression; irritability, aggression, or severely oppositional behaviours; behavioural (developmental) regression; deterioration in school performance; sensory or motor abnormalities; and somatic signs and symptoms, including sleep disturbances, enuresis, or urinary frequency. Criterion 3 Symptoms are not better explained by a known neurological or medical disorder, such as Sydenham chorea, systemic lupus erythematosus, Tourette disorder, or others. The diagnostic work-up of patients with suspected PANS must be comprehensive enough to rule out these and other relevant disorders. The nature of the co-occurring symptoms will dictate the necessary assessments, which may include MRI scans, lumbar puncture, electroencephalograms, or other diagnostic tests.
Participants (n=23) Age at PANS onset, years
8·5 (3·37)
Sex Boys
13 (57%)
Girls
10 (43%)
Pre-existing developmental disorder
5 (22%)
Pre-existing subclinical developmental problems
12 (52%)
Neuropsychiatric disorders in first-degree relatives
11 (48%)
Autoimmune or inflammatory diseases in first-degree relatives
11 (48%)
Streptococcal or other bacterial infection preceding PANS onset
10 (43%)
Viral infection preceding PANS onset
13 (57%)
Data are mean (SD) or n (%). PANS=paediatric acute-onset neuropsychiatric syndrome.
Table 1: Cohort characteristics
for nine patients, within 8–12 weeks for two patients, and uncertain for two patients. The mean PANS symptom score for the 23 patients was 46 (SD 3·67), and the mean impairment score was 45 (2·74). All children had acute onset of symptoms, with the full complex of symptoms appearing within 1–5 days. The median time since PANS onset was 3 years (range 3 months to 6 years). All children had severe obsessivecompulsive symptoms at PANS onset (as measured with
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Our cohort (n=23)
Stanford PANS cohort (n=19)10*
USF PANS cohort (n=43)11†
NIMH PANDAS cohort (n=48)16
23 (100%)
17 (89%)
43 (100%)
48 (100%)
5 (22%)
9 (47%)
20 (47%)
23 (48%)
Anxiety
21 (91%)
18 (95%)
43 (100%)
44 (92%)
Emotional lability or depression
21 (91%)
18 (95%)
43 (100%)
45 (94%)
Irritability or aggression
16 (70%)
15 (79%)
12 (28%)
20 (42%)
Behavioural regression
13 (57%)
11 (58%)
36 (84%)
30 (63%)
Academic deterioration
20 (87%)
16 (84%)
36 (84%)
36 (75%)
Sensory or motor problems
21 (91%)
18 (95%)
26 (60%)
37 (77%)
Major PANS criteria Obsessive-compulsive disorder Eating restriction Minor PANS criteria
Various specified symptoms Tics (simple or complex)
14 (61%)
5 (26%)
30 (70%)
32 (67%)
Simple tics
12 (52%)
4 (21%)
30 (70%)
NR
Complex tics
6 (26%)
1 (5%)
12 (28%)
NR
Chorea
0
1 (5%)
NR
Choreiform movements
4 (17%)
2 (11%)
9 (21%)
15 (65%)
11 (58%)
24 (56%)
25 (52%)
6 (26%)
4 (21%)
12 (28%)
13 (27%)
Urinary symptoms (urgency, enuresis) Psychotic symptoms (delusions, hallucinations)
NR NR
Fatigue
14 (61%)
11 (58%)
NR
NR
Sleep disturbance
19 (83%)
16 (84%)
36 (84%)
34 (71%)
PANS=paediatric acute-onset neuropsychiatric syndrome. USF=University of South Florida. NIMH=National Institute of Mental Health. PANDAS=paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. NR=not reported. *An additional 28 children in the Stanford study did not meet full criteria for PANS diagnosis but had symptoms that were similar to those of the children with PANS. †Some of the symptom categories in the USF report were different to those used in this study (ie, emotional lability or depression was mood and behavioural symptoms, irritability or aggression was aggressive behaviour, and the sensory or motor problems category was separated into sensory abnormalities [n=26] and visuospatial or motor impairment [n=28]), making these symptom ratings not directly comparable to those of the other cohorts.
Table 2: Frequency of PANS symptom criteria in our cohort compared with previous cohorts
the PANS scale), as well as four to 12 other symptoms (table 2). The most common symptoms, other than obsessive-compulsive symptoms, were anxiety, separation anxiety, or mood disorder; sensory or motor problems; and academic deterioration (table 2). A total of 17 different symptoms were recorded, including OCD, eating disorder, tics, anxiety or separation anxiety, depression, hyperactivity, attention problems, fine or gross motor problems, aggressiveness, irritability, urinary problems, sleeping disturbances, perceptual or sensory ab normalities, pupillary abnorm alities, deterioration of speech, general developmental regression, fatigue, and psychotic symptoms. Six children had psychotic symptoms (table 2), which occurred only temporarily during the worst symptom flares in all but two children who had more longstanding symptoms. Four children had choreiform movements of their fingers or hands, but none had more generalised chorea (table 2). During the most severe flares, all patients had severe obsessivecompulsive symptoms, meeting Diagnostic and Statistical 4
Manual of Mental Disorders 5 criteria for diagnosis of OCD. 17 children had pre-existing neurodevelopmental or behavioural problems (table 1), of whom five had been previously diagnosed with a specific neurodevelopmental or behavioural disorder (autism spectrum disorder in one, ADHD in two, and autism spectrum disorder and ADHD in two) and ten had subclinical problems (several symptoms of autism in two, hyperactivity in three, OCD symptoms in two, and anxiety in three). Another two children had very mild pre-existing problems (shyness or hyperactivity). Only six children had no preexisting neuropsychiatric problems. Medical laboratory assessments at paediatric clinics had been performed for 18 children and included magnetic resonance tomography (n=13), electroencephalogram (n=6), and CSF analyses of inflammatory biomarkers and anti-neuronal autoantibodies (n=6). The assessments were made on clinical grounds to exclude other medical or neurological conditions but not always with a documented suspicion of PANS. In no patient did the results of these investigations reveal a specific underlying cause of the neuropsychiatric symptoms. 14 children had severe symptoms that made school attendance impossible for several months, and eight had moderate to severe difficulties that required special measures (eg, individual support, small education groups, reduced number of school days, or shortened school days) to make some school attendance possible. In one child, the symptoms did not affect the school situation in any major aspect. All patients had been previously treated by a local paediatrician, paediatric neurologist, or child psychiatrist, and all had a relapsing–remitting course of illness. Four patients had not received any antibiotics or antimodulatory treatments since inflammatory or immuno onset of PANS because viral infections were suspected and their neuropsychiatric symptoms were not recognised as PANS. Between relapses, all four patients had remissions to medium symptom severity but did not reach low symptom severity. 19 patients had received antibiotics, of whom eight had short-term courses (<2 weeks) and 11 had long-term prophylaxis (from 1 month to several years; mostly phenoxymethylpenicillin or amoxicillin with or without clavulanic acid). When asked for their global impression of response to antibiotic treatment, most parents (63% [12/19]) reported good to very good responses (ie, reduction of symptoms to low severity or complete remission) and that symptom flares were common when treatment was discontinued. Between relapses, three of the 19 patients who received antibiotics had complete remission, with no remaining symptoms for 6 months or more, whereas symptoms were improved to low levels in nine patients and to medium levels in seven patients. In 20 of the 23 children, relapses were associated with infections. Owing to insufficient effect of antibiotics alone and symptom flares, five of the 19 children on antibiotics
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had also been treated with non-steroidal anti-inflammatory drugs (n=3; moderate to good effects were reported) or single doses of intravenous immunoglobulin (n=2; good to very good effects were reported).
Discussion This study included a group of 37 children who were referred to a specialist neuropsychiatric clinic with suspected PANS and four children who visited the clinic upon parents’ request. 23 children were found to meet diagnostic criteria for PANS.1 Because this is not a population-based cohort, no conclusions could be drawn about the prevalence of PANS. All children had acute PANS onset, as required by the diagnostic criteria, and a severe clinical picture during the most severe symptom flares, with high scores on the PANS symptom scale (mean score 46 [SD 3·67; range 36–50]) and impairment scale (45 [2·74; 40–50]). A similar impairment rating (44 [9; 20–50]) was reported for the Stanford PANS Clinic cohort of 19 children with PANS.10 The authors of that study10 also described a group of 28 children without PANS who had similar symptoms to the children with PANS but a subacute (3 days to 8 weeks) or insidious (>8 weeks) onset of symptoms and somewhat lower impairment ratings (mean score 39 [SD 13]; range 14–50]). In our study, all children had severe obsessivecompulsive symptoms, alongside several other symp toms, and a relapsing–remitting course of illness, with symptom flares often associated with infections. Similar symptom profiles as observed for our cohort were reported for the PANS cohort from Stanford,10 a PANS cohort from the University of South Florida (USF),11 and a PANDAS cohort from NIMH (table 2).16 More than half of the children in our group had periods of severe symptoms that made school attendance impossible for several months. 26% of our patients had psychotic symptoms, a similar proportion to those reported for the Stanford (21%) and USF (28%) cohorts. A study17 of 53 patients, including 13 adults, with suspected PANS or PANDAS in Sweden (of whom 24 met diagnostic criteria) reported visual hallucinations in 13 (25%) patients and auditory hallucinations in 12 (23%) patients. Six (26%) of 23 patients had hallucinations in our study, which were visual in six (26%) and auditory in five (22%). 61% of patients in our cohort had tics, which was similar to the proportions of patients with tics in the NIMH (67%) and USF (70%) cohorts but higher than the proportion of patients with tics in the Stanford cohort (26%; table 2). Another sign of neurological or motor abnormalities was choreiform movements, which were present in 17% of our patients, compared with 21% of patients in the USF cohort and 11% of patients in the Stanford cohort. A large survey of 698 patients with self-identified PANS or PANDAS reported global clinical pictures and a range of phenotypes but did not perform clinical examinations.18 74% of children in our cohort had a pre-existing neurodevelopmental disorder (ADHD or autism
spectrum disorder) or milder symptoms of anxiety, OCD, shyness, or hyperactivity, which might suggest that these patients are susceptible to neurodevelopmental or psychiatric problems. A similar proportion of patients with pre-existing neurodevelopmental or psychiatric problems (71%) was reported for the Stanford PANS cohort.10 A family history of autoimmune or inflammatory disorders was also common in our study and reported in first-degree relatives of 11 patients. Our cohort of patients will be followed up at the Child Neuropsychiatry Clinic with continued monitoring of symptom trajectories and treatment effects, and immuno logical, medical, and psychiatric assessments. These results will be presented in a future publication. A few patients have shown signs of developing autoimmune or inflammatory disease (gastrointestinal, diabetes, or possibly rheumatoid disorder). The main limitation of this study is recall bias, which might have occurred because ratings of symptoms, and descriptions of the speed of onset, its relation to infections, and the response of patients to antibiotics, were made retrospectively through interviews with parents and patients. For several patients, some years had passed between symptom onset and assessment at our clinic. Other limitations include the small cohort size and potential for selection bias, which do not permit conclusions to be made about prevalence, and that cases might not be representative of all children with PANS. Previous medical evaluations and laboratory tests varied between patients because they were performed on clinical grounds, were not always made at symptom onset, and suspicion of PANS sometimes came later. In conclusion, the children and adolescents in our PANS cohort had a complex mix of psychiatric and neurological symptoms, which commonly included regression in motor and cognitive abilities and developed after an infection. All patients had a relapsing–remitting course of illness, with symptom flares usually related to infections. Impairments in daily life and academic performance were very severe during the most severe symptom flares. Overall, the symptom profiles of our patients were similar to those of patients in previously described clinical cohorts from North America.10,11,16 Many parents reported that their child had a good response to antibiotic treatment, with some having long periods of complete remission or low-level symptoms. Previous medical assessments and biomarker tests had not revealed any specific underlying cause for the symptoms, and further research is needed to clarify the underlying mechanisms of the condition and to identify treatment options. Seven of our patients had PANS-like, acuteonset complex neuropsychiatric symptoms in the absence of the obsessive-compulsive component. This finding suggests that there might be a broader spectrum of neuroinflammatory conditions than the cases included in the PANS cohort. We agree with the PANS Research Consortium10 that the complex symptomatology of these
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patients, including psychiatric, neurological, infectious, and immunological factors, requires a multidisciplinary approach to assessment and treatment.
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Contributors All authors contributed to study design, data analysis, data interpretation, and drafting and revision of the manuscript, and gave final approval of the version to be submitted for publication.
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Declaration of interests MJ has received research grants from Shire and Vifor Pharma and been engaged as a speaker or consultant by Eli Lilly, Shire, Vifor Pharma, Ginsana, PCM Scientific, Evolan, and New Nordic. AF has received research grants from Shire and been engaged as a speaker or consultant by Shire, AbbVie, Janssen, and Lipum. All other authors declare no competing interests. Acknowledgments The study was supported by an unrestricted research grant from Swedish Brain Foundation. We thank Susan Swedo and James Leckman for their valuable advice and permission to use the PANS scale and all participating families for their contributions. References 1 Swedo SE, Leckman JF, Rose NR. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (pediatric acute-onset neuropsychiatric syndrome). Pediatr Therapeut 2012; 2: 113–21. 2 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: 264–71. 3 Chang K, Frankovich J, Cooperstock M, et al. Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol 2015; 25: 3–13. 4 Cooperstock M, Swedo S, Pasternack M, et al. Clinical management of pediatric acute-onset neuropsychiatric syndrome: part III—treatment and prevention of infections. J Child Adolesc Psychopharmacol 2017; 27: 594–606. 5 Frankovich J, Swedo S, Murphy T, et al. Clinical management of pediatric acute-onset neuropsychiatric syndrome: part II—use of immunomodulatory therapies. J Child Adolesc Psychopharmacol 2017; 27: 1–16. 6 Swedo SE, Frankovich J, Murphy TK. Overview of treatment of pediatric acute-onset neuropsychiatric syndrome. J Child Adolesc Psychopharmacol 2017; 27: 562–65.
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Thienemann M, Murphy T, Leckman J, et al. Clinical management of pediatric acute-onset neuropsychiatric syndrome: part I— psychiatric and behavioral interventions. J Child Adolesc Psychopharmacol 2017; 27: 566–73. Gilbert DL, Mink JW, Singer HS. A pediatric neurology perspective on pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection and pediatric acute-onset neuropsychiatric syndrome. J Pediatrics 2018; 199: 243–51. Frankovich J, Thienemann M, Rana S, et al. Five youth with pediatric acute-onset neuropsychiatric syndrome of differing etiologies. J Child Adolesc Psychopharmacol 2015; 25: 31–37. Frankovich J, Thienemann M, Pearlstein J, Crable A, Brown K, Chang K. Multidisciplinary clinic dedicated to treating youth with pediatric acute-onset neuropsychiatric syndrome: presenting characteristics of the first 47 consecutive patients. J Child Adolesc Psychopharmacol 2015; 25: 38–47. Murphy TK, Patel PD, McGuire JF, et al. Characterization of the pediatric acute-onset neuropsychiatric syndrome phenotype. J Child Adolesc Psychopharmacol 2015; 25: 14–25. Macerollo A, Martino D. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS): an evolving concept. Tremor Other Hyperkinet Mov 2013; 3: tre-03-167-4158-7. Snider LA, Lougee L, Slattery M, et al. Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders. Biol Psychiatry 2005; 57: 788–92. Sigra S, Hesselmark E, Bejerot S. Treatment of PANDAS and PANS: a systematic review. Neurosci Biobehav Rev 2018; 86: 51–65. Socialstyrelsen. Nationella riktlinjer för vård vid depression och ångestsyndrom. 2017. https://www.socialstyrelsen.se/ publikationer2017/2017-12-4 (accessed Nov 14, 2018). Swedo SE, Seidlitz J, Kovacevic M, et al. Clinical presentation of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections in research and community settings. J Child Adolesc Psychopharmacol 2015; 25: 26–30. Hesselmark E, Bejerot S. Biomarkers for diagnosis of pediatric acute neuropsychiatric syndrome (PANS)—sensitivity and specificity of the Cunningham Panel. J Neuroimmunol 2017; 312: 31–37. Calaprice D, Tona J, Parker-Athill EC, Murphy TK. A survey of pediatric acute-onset neuropsychiatric syndrome characteristics and course. J Child Adolesc Psychopharmacol 2017; 27: 607–18.
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Paediatric acute-onset neuropsychiatric syndrome in children and adolescents: an observational cohort study Mats Johnson, Elisabeth Fernell, Iulian Preda, Lena Wallin, Anders Fasth, Carina Gillberg, Christopher Gillberg
Summary
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.
Lancet Child Adolesc Health 2019 Published Online January 28, 2019 http://dx.doi.org/10.1016/ S2352-4642(18)30404-8 See Online/Comment http://dx.doi.org/10.1016/ S2352-4642(19)30021-5 Gillberg Neuropsychiatry Centre (M Johnson MD, Prof E Fernell MD, L Wallin MD, Ca Gillberg MD, Prof Ch Gillberg MD) and Department of Paediatrics, Institute of Clinical Sciences (I Preda MD, Prof A Fasth MD), Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden Correspondence to: Dr Mats Johnson, Gillberg Neuropsychiatry Centre, Sahlgrenska Academy, Gothenburg University, 411 19 Gothenburg, Sweden [email protected]
Funding Swedish Brain Foundation. Copyright © 2019 Elsevier Ltd. All rights reserved.
Introduction Paediatric acute-onset neuropsychiatric syndrome (PANS) is characterised by abrupt onset of a broad range of neuropsychiatric symptoms.1 PANS has increasingly replaced the term paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)2 to focus entirely on symptoms, given that several infectious agents other than streptococci, as well as mechanisms other than infection, might be involved in the disorder. PANDAS is specifically linked to streptococcal infections and now considered to be a subgroup of PANS. Diagnosis of PANS is done by exclusion;1,3–7 it is diagnosed only when symptoms are not better explained by a known neurological, medical, or psychiatric disorder.1,6 Criteria for PANS, and guidelines for its assessment and treatment, have been published by the PANS Research Consortium.1,3–7 According to this definition, PANS onset is acute and dramatic, and includes obsessive-compulsive disorder (OCD) or eating restriction, and at least two other coinciding symptoms (panel). PANS has been linked to several different disease mechanisms, including neurological, endocrine, and metabolic processes, and post-infectious autoimmune
and neuroinflammatory disorders.1,3,8 In a case series of five patients, Frankovich and colleagues9 described five different infectious or autoimmune causes of the syndrome. Neuroinflammation is postulated to have a part in the initiation and progression of symptoms in most patients, with some case series documenting immune abnormalities in more than 80% of patients.10,11 However, in many patients, the definite cause cannot be identified by clinical investigations, laboratory tests, or cerebral imaging. Macerollo and Martino12 argued that the evidence for a post-infectious, immune-mediated patho physiology is insufficient and that larger, prospective studies are needed to reshape the nosography of PANS and identify the underlying mechanisms of the condition. Similarly, a report7 by the PANS Research Consortium stated that additional research is needed to understand the clinical heterogeneity of the condition. Treatment of PANS includes antimicrobial inter ventions and immunomodulatory or anti-inflammatory therapies that are given alongside supportive inter ventions (eg, family and school support), psychoactive medications, and cognitive behavioural therapy.6 These treatments have been reported to reduce or eliminate
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Research in context Evidence before this study Paediatric acute-onset neuropsychiatric syndrome (PANS) is a recently described clinical condition defined by acute onset of a broad spectrum of neuropsychiatric symptoms. Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is considered to be a subgroup of PANS. Proposed triggers of PANS are infections and inflammatory and autoimmune reactions. Using the search terms “PANS” and “PANDAS”, we searched PubMed without language restrictions up to Nov 1, 2018, for articles related to these conditions. We found few detailed descriptions of clinical cohorts, which were mainly from North America. We also found reviews of studies of treatments for PANS, which reported variable and inconclusive results. Added value of this study This study is among the first to describe a cohort of patients with PANS from a European country. The symptom profiles of
For the PANS scale see http://www.nepans.org/ uploads/8/1/4/0/81404234/ pandas_pans_scale.pdf
symptoms,4–7,13 but are ineffective in some patients, with some having ongoing symptoms that require continuous intervention and support.7 Initial treatment with antibiotics is recommended by the PANS Research Consortium for all patients with PANS, including those without documented infections. This recommendation is supported by extensive clinical experience from a large number of patients of PANS symptom improve ment with antibiotics, including reports of patients who have had complete and lasting remission of symptoms during antibiotic treatment.4,6,11 However, in a 2018 systematic review of available case reports and trials, Sigra and colleagues14 concluded that the evidence for using antibiotics is inconclusive. Similarly, Swedish national guidelines, published by the National Board of Health and Welfare in 2017,15 concluded that the scientific evidence for the treatment of PANS is insufficient. Evaluation of treatment might also be complicated by the fact that patients can have a relapsing–remitting, chronic–static, or chronic–pro gressive course of illness. The aim of this study was to report data from a group of children and adolescents with suspected PANS who were referred to a specialist centre in Sweden for clinical evaluation, and to compare the symptom profiles and trajectories of these patients with those of pre viously described cohorts, mainly from North America.
Methods
Study participants Patients were children and adolescents (aged 4–14 years), mostly from the southwestern part of Sweden, who were referred to the Child Neuropsychiatry Clinic, associated with the Gillberg Neuropsychiatry Centre, Gothenburg, 2
our patients, who were from Sweden, were similar to those described for North American cohorts and included acute onset of psychiatric and neurological symptoms, regression in cognitive and motor abilities, a relapsing–remitting symptom course, with periods of relapse related to infections, and periodically severe impairments in daily life. In all patients, onset of PANS occurred after a bacterial or viral infection, and many parents reported that their children had responded well to antibiotic treatment, with long periods of partial or complete remission of symptoms. Implications of all the available evidence Our findings are consistent with previous observations of distinct symptom profiles and trajectories for patients with PANS and support a post-infectious mechanism for the condition and possible beneficial effects of antibiotic treatment.
Sweden, between Feb 1, 2015, and Dec 31, 2017, by their local paediatrician or child psychiatrist. The study was approved by the local ethical review board. All parents and participants provided informed consent after receiving a complete description of the study.
Procedures Parents were interviewed in a semi-structured manner about family histories of developmental or neuro psychiatric disorders (eg, attention deficit hyperactivity disorder [ADHD], autism spectrum disorder, OCD, anorexia, depression, anxiety, or learning difficulties) and autoimmune or inflammatory disorders, the child’s early development, previous assessments, and medical and psychiatric histories. We also collected information about the timing and nature of the symptoms that led to suspicion of PANS; potential triggers, such as infections; and previous treatments. Previous medical records were reviewed. All patients were assessed by EF and MJ at a clinical visit. Severity of symptoms and impairment was rated by the investigators during interviews with parents and patients using the PANS scale, which was developed by Swedo, Leckman, and colleagues (National Institute of Mental Health [NIMH], personal communication). On the scale, each symptom included in the PANS criteria is scored from 0 to 5 points (none to very severe), with a total score range of 0–50 points. The impairment part of the scale estimates impairment in self-esteem, family life, social acceptance, and school or job functioning, with a total score range of 0–50 points (none to extreme difficulties). Onset of PANS had occurred several months or years before the study in many patients, and symptom ratings for the most severe period were made retro spectively. Parents of children who had received antibiotics
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were asked for their global impression of treatment response.
Statistical analysis We used descriptive statistics to summarise quantitative data and calculated means and SDs for PANS scale symptom and impairment scores.
Role of the funding source The funder of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results 37 patients were referred to the Child Neuropsychiatry Clinic between Feb 1, 2015, and Dec 31, 2017, by their local paediatrician, paediatric neurologist, or child psychiatrist, and four were included after their parents contacted the clinic following their child’s assessment by a local paediatrician or child psychiatrist. Of these, 23 patients (13 boys and ten girls), with a mean age at PANS onset of 8·5 years (SD 3·37; range 3–14), met diagnostic criteria for PANS (panel).1 18 children did not meet PANS criteria—for example, they did not have typical acute onset with complex symptoms or had other neurological or neuropsychiatric symptoms, such as regressive autism, epilepsy, or other identified neuro logical or neuro psychiatric disorders. Seven of these children had acute, post-infectious onset with symptoms such as irritability, anxiety, regression, motor or sensory abnormalities, tics, and fatigue, but did not have the obsessive-compulsive component necessary for PANS diagnosis. 11 children had a family history of developmental or neuropsychiatric disorders in a first-degree relative and 11 had a family history of autoimmune or inflammatory diseases in a first-degree relative (table 1). For two children, autoimmune or inflammatory disorders were described in more than one first-degree relative (ie, one child had two family members with ulcerative colitis, and the other had one family member with hypothyroidism and one with type 1 diabetes), whereas nine children had one family member with an autoimmune or inflammatory disorder (including coeliac disease, psoriasis, Crohn’s disease, Guillain-Barré syndrome, multiple sclerosis, rheumatoid disorder, type 1 diabetes, IgA vasculitis [also known as Henoch-Schönlein purpura], or thyroid disorder). In ten children, PANS onset was preceded (within 4 weeks) by a suspected (n=2) or verified (n=6) streptococcal infection or by an infection caused by a non-streptococcal bacterium (n=2; including an upper respiratory infection in one child and otitis media in the other; table 1). 13 children had a suspected viral infection before onset of PANS (table 1); the timing of this infection, as related to PANS onset, was within 4 weeks
Panel: Diagnostic criteria for paediatric acute-onset neuropsychiatric syndrome (PANS)1 Criterion 1 Abrupt, dramatic onset of obsessive-compulsive disorder or severely restricted food intake. Criterion 2 Concurrent presence of additional neuropsychiatric symptoms, with similarly severe and acute onset, from at least two of the following seven categories: anxiety; emotional lability or depression; irritability, aggression, or severely oppositional behaviours; behavioural (developmental) regression; deterioration in school performance; sensory or motor abnormalities; and somatic signs and symptoms, including sleep disturbances, enuresis, or urinary frequency. Criterion 3 Symptoms are not better explained by a known neurological or medical disorder, such as Sydenham chorea, systemic lupus erythematosus, Tourette disorder, or others. The diagnostic work-up of patients with suspected PANS must be comprehensive enough to rule out these and other relevant disorders. The nature of the co-occurring symptoms will dictate the necessary assessments, which may include MRI scans, lumbar puncture, electroencephalograms, or other diagnostic tests.
Participants (n=23) Age at PANS onset, years
8·5 (3·37)
Sex Boys
13 (57%)
Girls
10 (43%)
Pre-existing developmental disorder
5 (22%)
Pre-existing subclinical developmental problems
12 (52%)
Neuropsychiatric disorders in first-degree relatives
11 (48%)
Autoimmune or inflammatory diseases in first-degree relatives
11 (48%)
Streptococcal or other bacterial infection preceding PANS onset
10 (43%)
Viral infection preceding PANS onset
13 (57%)
Data are mean (SD) or n (%). PANS=paediatric acute-onset neuropsychiatric syndrome.
Table 1: Cohort characteristics
for nine patients, within 8–12 weeks for two patients, and uncertain for two patients. The mean PANS symptom score for the 23 patients was 46 (SD 3·67), and the mean impairment score was 45 (2·74). All children had acute onset of symptoms, with the full complex of symptoms appearing within 1–5 days. The median time since PANS onset was 3 years (range 3 months to 6 years). All children had severe obsessivecompulsive symptoms at PANS onset (as measured with
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Our cohort (n=23)
Stanford PANS cohort (n=19)10*
USF PANS cohort (n=43)11†
NIMH PANDAS cohort (n=48)16
23 (100%)
17 (89%)
43 (100%)
48 (100%)
5 (22%)
9 (47%)
20 (47%)
23 (48%)
Anxiety
21 (91%)
18 (95%)
43 (100%)
44 (92%)
Emotional lability or depression
21 (91%)
18 (95%)
43 (100%)
45 (94%)
Irritability or aggression
16 (70%)
15 (79%)
12 (28%)
20 (42%)
Behavioural regression
13 (57%)
11 (58%)
36 (84%)
30 (63%)
Academic deterioration
20 (87%)
16 (84%)
36 (84%)
36 (75%)
Sensory or motor problems
21 (91%)
18 (95%)
26 (60%)
37 (77%)
Major PANS criteria Obsessive-compulsive disorder Eating restriction Minor PANS criteria
Various specified symptoms Tics (simple or complex)
14 (61%)
5 (26%)
30 (70%)
32 (67%)
Simple tics
12 (52%)
4 (21%)
30 (70%)
NR
Complex tics
6 (26%)
1 (5%)
12 (28%)
NR
Chorea
0
1 (5%)
NR
Choreiform movements
4 (17%)
2 (11%)
9 (21%)
15 (65%)
11 (58%)
24 (56%)
25 (52%)
6 (26%)
4 (21%)
12 (28%)
13 (27%)
Urinary symptoms (urgency, enuresis) Psychotic symptoms (delusions, hallucinations)
NR NR
Fatigue
14 (61%)
11 (58%)
NR
NR
Sleep disturbance
19 (83%)
16 (84%)
36 (84%)
34 (71%)
PANS=paediatric acute-onset neuropsychiatric syndrome. USF=University of South Florida. NIMH=National Institute of Mental Health. PANDAS=paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. NR=not reported. *An additional 28 children in the Stanford study did not meet full criteria for PANS diagnosis but had symptoms that were similar to those of the children with PANS. †Some of the symptom categories in the USF report were different to those used in this study (ie, emotional lability or depression was mood and behavioural symptoms, irritability or aggression was aggressive behaviour, and the sensory or motor problems category was separated into sensory abnormalities [n=26] and visuospatial or motor impairment [n=28]), making these symptom ratings not directly comparable to those of the other cohorts.
Table 2: Frequency of PANS symptom criteria in our cohort compared with previous cohorts
the PANS scale), as well as four to 12 other symptoms (table 2). The most common symptoms, other than obsessive-compulsive symptoms, were anxiety, separation anxiety, or mood disorder; sensory or motor problems; and academic deterioration (table 2). A total of 17 different symptoms were recorded, including OCD, eating disorder, tics, anxiety or separation anxiety, depression, hyperactivity, attention problems, fine or gross motor problems, aggressiveness, irritability, urinary problems, sleeping disturbances, perceptual or sensory ab normalities, pupillary abnorm alities, deterioration of speech, general developmental regression, fatigue, and psychotic symptoms. Six children had psychotic symptoms (table 2), which occurred only temporarily during the worst symptom flares in all but two children who had more longstanding symptoms. Four children had choreiform movements of their fingers or hands, but none had more generalised chorea (table 2). During the most severe flares, all patients had severe obsessivecompulsive symptoms, meeting Diagnostic and Statistical 4
Manual of Mental Disorders 5 criteria for diagnosis of OCD. 17 children had pre-existing neurodevelopmental or behavioural problems (table 1), of whom five had been previously diagnosed with a specific neurodevelopmental or behavioural disorder (autism spectrum disorder in one, ADHD in two, and autism spectrum disorder and ADHD in two) and ten had subclinical problems (several symptoms of autism in two, hyperactivity in three, OCD symptoms in two, and anxiety in three). Another two children had very mild pre-existing problems (shyness or hyperactivity). Only six children had no preexisting neuropsychiatric problems. Medical laboratory assessments at paediatric clinics had been performed for 18 children and included magnetic resonance tomography (n=13), electroencephalogram (n=6), and CSF analyses of inflammatory biomarkers and anti-neuronal autoantibodies (n=6). The assessments were made on clinical grounds to exclude other medical or neurological conditions but not always with a documented suspicion of PANS. In no patient did the results of these investigations reveal a specific underlying cause of the neuropsychiatric symptoms. 14 children had severe symptoms that made school attendance impossible for several months, and eight had moderate to severe difficulties that required special measures (eg, individual support, small education groups, reduced number of school days, or shortened school days) to make some school attendance possible. In one child, the symptoms did not affect the school situation in any major aspect. All patients had been previously treated by a local paediatrician, paediatric neurologist, or child psychiatrist, and all had a relapsing–remitting course of illness. Four patients had not received any antibiotics or antimodulatory treatments since inflammatory or immuno onset of PANS because viral infections were suspected and their neuropsychiatric symptoms were not recognised as PANS. Between relapses, all four patients had remissions to medium symptom severity but did not reach low symptom severity. 19 patients had received antibiotics, of whom eight had short-term courses (<2 weeks) and 11 had long-term prophylaxis (from 1 month to several years; mostly phenoxymethylpenicillin or amoxicillin with or without clavulanic acid). When asked for their global impression of response to antibiotic treatment, most parents (63% [12/19]) reported good to very good responses (ie, reduction of symptoms to low severity or complete remission) and that symptom flares were common when treatment was discontinued. Between relapses, three of the 19 patients who received antibiotics had complete remission, with no remaining symptoms for 6 months or more, whereas symptoms were improved to low levels in nine patients and to medium levels in seven patients. In 20 of the 23 children, relapses were associated with infections. Owing to insufficient effect of antibiotics alone and symptom flares, five of the 19 children on antibiotics
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had also been treated with non-steroidal anti-inflammatory drugs (n=3; moderate to good effects were reported) or single doses of intravenous immunoglobulin (n=2; good to very good effects were reported).
Discussion This study included a group of 37 children who were referred to a specialist neuropsychiatric clinic with suspected PANS and four children who visited the clinic upon parents’ request. 23 children were found to meet diagnostic criteria for PANS.1 Because this is not a population-based cohort, no conclusions could be drawn about the prevalence of PANS. All children had acute PANS onset, as required by the diagnostic criteria, and a severe clinical picture during the most severe symptom flares, with high scores on the PANS symptom scale (mean score 46 [SD 3·67; range 36–50]) and impairment scale (45 [2·74; 40–50]). A similar impairment rating (44 [9; 20–50]) was reported for the Stanford PANS Clinic cohort of 19 children with PANS.10 The authors of that study10 also described a group of 28 children without PANS who had similar symptoms to the children with PANS but a subacute (3 days to 8 weeks) or insidious (>8 weeks) onset of symptoms and somewhat lower impairment ratings (mean score 39 [SD 13]; range 14–50]). In our study, all children had severe obsessivecompulsive symptoms, alongside several other symp toms, and a relapsing–remitting course of illness, with symptom flares often associated with infections. Similar symptom profiles as observed for our cohort were reported for the PANS cohort from Stanford,10 a PANS cohort from the University of South Florida (USF),11 and a PANDAS cohort from NIMH (table 2).16 More than half of the children in our group had periods of severe symptoms that made school attendance impossible for several months. 26% of our patients had psychotic symptoms, a similar proportion to those reported for the Stanford (21%) and USF (28%) cohorts. A study17 of 53 patients, including 13 adults, with suspected PANS or PANDAS in Sweden (of whom 24 met diagnostic criteria) reported visual hallucinations in 13 (25%) patients and auditory hallucinations in 12 (23%) patients. Six (26%) of 23 patients had hallucinations in our study, which were visual in six (26%) and auditory in five (22%). 61% of patients in our cohort had tics, which was similar to the proportions of patients with tics in the NIMH (67%) and USF (70%) cohorts but higher than the proportion of patients with tics in the Stanford cohort (26%; table 2). Another sign of neurological or motor abnormalities was choreiform movements, which were present in 17% of our patients, compared with 21% of patients in the USF cohort and 11% of patients in the Stanford cohort. A large survey of 698 patients with self-identified PANS or PANDAS reported global clinical pictures and a range of phenotypes but did not perform clinical examinations.18 74% of children in our cohort had a pre-existing neurodevelopmental disorder (ADHD or autism
spectrum disorder) or milder symptoms of anxiety, OCD, shyness, or hyperactivity, which might suggest that these patients are susceptible to neurodevelopmental or psychiatric problems. A similar proportion of patients with pre-existing neurodevelopmental or psychiatric problems (71%) was reported for the Stanford PANS cohort.10 A family history of autoimmune or inflammatory disorders was also common in our study and reported in first-degree relatives of 11 patients. Our cohort of patients will be followed up at the Child Neuropsychiatry Clinic with continued monitoring of symptom trajectories and treatment effects, and immuno logical, medical, and psychiatric assessments. These results will be presented in a future publication. A few patients have shown signs of developing autoimmune or inflammatory disease (gastrointestinal, diabetes, or possibly rheumatoid disorder). The main limitation of this study is recall bias, which might have occurred because ratings of symptoms, and descriptions of the speed of onset, its relation to infections, and the response of patients to antibiotics, were made retrospectively through interviews with parents and patients. For several patients, some years had passed between symptom onset and assessment at our clinic. Other limitations include the small cohort size and potential for selection bias, which do not permit conclusions to be made about prevalence, and that cases might not be representative of all children with PANS. Previous medical evaluations and laboratory tests varied between patients because they were performed on clinical grounds, were not always made at symptom onset, and suspicion of PANS sometimes came later. In conclusion, the children and adolescents in our PANS cohort had a complex mix of psychiatric and neurological symptoms, which commonly included regression in motor and cognitive abilities and developed after an infection. All patients had a relapsing–remitting course of illness, with symptom flares usually related to infections. Impairments in daily life and academic performance were very severe during the most severe symptom flares. Overall, the symptom profiles of our patients were similar to those of patients in previously described clinical cohorts from North America.10,11,16 Many parents reported that their child had a good response to antibiotic treatment, with some having long periods of complete remission or low-level symptoms. Previous medical assessments and biomarker tests had not revealed any specific underlying cause for the symptoms, and further research is needed to clarify the underlying mechanisms of the condition and to identify treatment options. Seven of our patients had PANS-like, acuteonset complex neuropsychiatric symptoms in the absence of the obsessive-compulsive component. This finding suggests that there might be a broader spectrum of neuroinflammatory conditions than the cases included in the PANS cohort. We agree with the PANS Research Consortium10 that the complex symptomatology of these
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patients, including psychiatric, neurological, infectious, and immunological factors, requires a multidisciplinary approach to assessment and treatment.
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Contributors All authors contributed to study design, data analysis, data interpretation, and drafting and revision of the manuscript, and gave final approval of the version to be submitted for publication.
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Declaration of interests MJ has received research grants from Shire and Vifor Pharma and been engaged as a speaker or consultant by Eli Lilly, Shire, Vifor Pharma, Ginsana, PCM Scientific, Evolan, and New Nordic. AF has received research grants from Shire and been engaged as a speaker or consultant by Shire, AbbVie, Janssen, and Lipum. All other authors declare no competing interests. Acknowledgments The study was supported by an unrestricted research grant from Swedish Brain Foundation. We thank Susan Swedo and James Leckman for their valuable advice and permission to use the PANS scale and all participating families for their contributions. References 1 Swedo SE, Leckman JF, Rose NR. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (pediatric acute-onset neuropsychiatric syndrome). Pediatr Therapeut 2012; 2: 113–21. 2 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: 264–71. 3 Chang K, Frankovich J, Cooperstock M, et al. Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol 2015; 25: 3–13. 4 Cooperstock M, Swedo S, Pasternack M, et al. Clinical management of pediatric acute-onset neuropsychiatric syndrome: part III—treatment and prevention of infections. J Child Adolesc Psychopharmacol 2017; 27: 594–606. 5 Frankovich J, Swedo S, Murphy T, et al. Clinical management of pediatric acute-onset neuropsychiatric syndrome: part II—use of immunomodulatory therapies. J Child Adolesc Psychopharmacol 2017; 27: 1–16. 6 Swedo SE, Frankovich J, Murphy TK. Overview of treatment of pediatric acute-onset neuropsychiatric syndrome. J Child Adolesc Psychopharmacol 2017; 27: 562–65.
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Thienemann M, Murphy T, Leckman J, et al. Clinical management of pediatric acute-onset neuropsychiatric syndrome: part I— psychiatric and behavioral interventions. J Child Adolesc Psychopharmacol 2017; 27: 566–73. Gilbert DL, Mink JW, Singer HS. A pediatric neurology perspective on pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection and pediatric acute-onset neuropsychiatric syndrome. J Pediatrics 2018; 199: 243–51. Frankovich J, Thienemann M, Rana S, et al. Five youth with pediatric acute-onset neuropsychiatric syndrome of differing etiologies. J Child Adolesc Psychopharmacol 2015; 25: 31–37. Frankovich J, Thienemann M, Pearlstein J, Crable A, Brown K, Chang K. Multidisciplinary clinic dedicated to treating youth with pediatric acute-onset neuropsychiatric syndrome: presenting characteristics of the first 47 consecutive patients. J Child Adolesc Psychopharmacol 2015; 25: 38–47. Murphy TK, Patel PD, McGuire JF, et al. Characterization of the pediatric acute-onset neuropsychiatric syndrome phenotype. J Child Adolesc Psychopharmacol 2015; 25: 14–25. Macerollo A, Martino D. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS): an evolving concept. Tremor Other Hyperkinet Mov 2013; 3: tre-03-167-4158-7. Snider LA, Lougee L, Slattery M, et al. Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders. Biol Psychiatry 2005; 57: 788–92. Sigra S, Hesselmark E, Bejerot S. Treatment of PANDAS and PANS: a systematic review. Neurosci Biobehav Rev 2018; 86: 51–65. Socialstyrelsen. Nationella riktlinjer för vård vid depression och ångestsyndrom. 2017. https://www.socialstyrelsen.se/ publikationer2017/2017-12-4 (accessed Nov 14, 2018). Swedo SE, Seidlitz J, Kovacevic M, et al. Clinical presentation of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections in research and community settings. J Child Adolesc Psychopharmacol 2015; 25: 26–30. Hesselmark E, Bejerot S. Biomarkers for diagnosis of pediatric acute neuropsychiatric syndrome (PANS)—sensitivity and specificity of the Cunningham Panel. J Neuroimmunol 2017; 312: 31–37. Calaprice D, Tona J, Parker-Athill EC, Murphy TK. A survey of pediatric acute-onset neuropsychiatric syndrome characteristics and course. J Child Adolesc Psychopharmacol 2017; 27: 607–18.
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