Researchers have suggested a new component to the long controversial diagnosis of paediatric acute-onset neuropsychiatric syndrome (PANS) – along with the related paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).
The analysis of nearly 200 children with PANS found a substantial proportion with “subtle, systemic inflammation”, raising the possibility that the psychiatric symptoms reflect a brain response to a global process, according to Jennifer Frankovich, MD, of Stanford and colleagues, whose findings were published in JAMA Network Open.
They noted a heightened risk of arthritis in their cohort and concluded that PANS “may be part of a multi-system inflammatory condition rather than an isolated psychiatric or neuro-inflammatory disorder”, reports Medpage Today.
The term PANDAS was coined in 1998 when a team at the National Institute of Mental Health described 50 children who abruptly developed obsessive-compulsive disorder (OCD) features or tics after exposure to group A streptococcus, according to J Patrick Whelan, MD, PhD, of the University of California-Los Angeles, who wrote an accompanying invited commentary.
PANS is more broad, with the rapid onset of OCD symptoms following any type of infection, not just strep. Those symptoms are often accompanied by sleep disruption, urinary changes, cognitive and behavioural problems and emotional imbalance.
Yet few physicians are trained to recognise the condition, said Aravindhan Veerapandiyan, MD, a paediatric neurologist at Arkansas Children’s Hospital who co-directs its Childhood Post-infectious Autoimmune Encephalopathy Centre of Excellence.
“It’s still a controversial diagnosis, and still a lot of providers out there who don’t believe that (PANS and PANDAS) exist,” Veerapandiyan told MedPage Today.
Some of the reasons for that scepticism include “a lot of not-so-evidence-based practice” as well as a lack of established biomarkers to confirm the diagnosis, he said.
Still, researchers know more about the condition than they did two decades ago. The prevailing theory is that an infection triggers certain antibodies that cross the blood-brain barrier and cause inflammation in the brain, particularly in the basal ganglia.
The study from Frankovich and colleagues evaluated 193 patients with PANS who were treated at their clinic from September 2012 to December 2021. The mean age was 7.5 years and the children were followed for a mean of four years. More than half were boys (58%) and 83% were white.
They found that 54% had non-specific markers of autoimmunity, while just 12% had markers of immune dysregulation or inflammation. Also, 36% had signs of vasculopathy.
More than a quarter (28.3%) developed arthritis by age 14. Among them, around two-thirds met criteria for enthesitis-related arthritis, which affects joints of the lower extremities, and nearly half met criteria for spondyloarthritis, characterised by inflammation in the spine.
Furthermore, 7.5% went on to develop another autoimmune condition.
Whelan wrote in his commentary that the children who developed arthritis displayed an “unusual rheumatic disease profile”, with 56% showing Achilles enthesitis, 64% with inflammatory back pain, and 69% with sacroiliac joint tenderness. Just 2% of the cohort “developed the more typical childhood forms of arthritis, namely systemic lupus or juvenile idiopathic arthritis”, he wrote.
“It validates an observation I’ve made in our practice, which is that a relatively large number of children in this population have a very particular kind of arthritis that they develop.”
He said he has had success treating youngsters with PANS/PANDAS, based on this model: “This is something neurologists would never have thought to do, which is to put kids like this on an arthritis medicine. But all of a sudden, they’re going to school again, they’re productive citizens, and they eventually – a lot of them – grow out of the behavioural issues.”
But Veerapandiyan isn’t so sure about that. Though he agreed that PANS is an autoimmune inflammatory condition, within his patient population, “I haven’t noticed anyone developing rheumatoid arthritis or other types of inflammatory conditions that are manifesting clinically”, he said.
He noted that Frankovich, the senior author and director of the clinic from where the patient population was drawn, is a rheumatologist, “so the patients seen in the clinic are most likely going to have some sort of rheumatological problems”.
Frankovich emphasised that their study did not find any cases of rheumatoid arthritis. “The arthritis we see is dry and does not manifest clinically. And since the psychiatric symptoms are overwhelming, the patients do not complain of low-grade joint pain,” she told MedPage Today.
Once her patients are treated with immunomodulators, she added, they can begin to tolerate other treatments that then seem to work better, like cognitive behavioural therapy, tic reversal therapy, and selective serotonin reuptake inhibitors.
Veerapandiyan also cautioned that without a control group, it’s hard to know how the inflammatory profiles compare to those in people without PANS/PANDAS.
“This is good information,” he said, but added that he doesn’t now plan to test his current case for the laboratory markers evaluated in the study.
Whelan said he sees children whose symptoms may have emerged after other infections like Covid, who in the past may not have fit neatly into either psychiatry or neurology treatment.
“So like many other things, like long Covid, for instance…it’s kind of fallen to the rheumatologist, because we’re really the consultants of last resort.”
Parents and patients with PANS/PANDAS often describe frustrating medical encounters typified by scepticism, unfamiliarity, and difficulty diagnosing what may look like OCD or bipolar disorder. Some major paediatric hospitals even specify that they will not see PANS/PANDAS patients.
Veerapandiyan, who usually deploys antibiotics, anti-inflammatories, and steroids to treat the condition, said immune-suppressants have also shown promise, anecdotally. He’s also leading a clinical trial of intravenous immunoglobulin for the condition.
More research on PANS/PANDAS is needed, he said. “There should also be more efforts to actually create awareness and education of more appropriate information for families and providers.”
Study details
Development of Autoimmune Diseases Among Children With Pediatric Acute-Onset Neuropsychiatric Syndrome
Meiqian Ma, Erin Masterson, Jaynelle Gao, et al.
Published in JAMA Network Open on 30 July 2024
Abstract
Importance
Epidemiologic studies indicate a high rate of autoimmune conditions among patients with obsessive-compulsive disorder and other psychiatric conditions. Furthering the understanding of the inflammatory diatheses of psychiatric conditions may open doors to new treatment paradigms for psychiatric disorders.
Objectives
To evaluate whether paediatric acute-onset neuropsychiatric syndrome (PANS) is associated with an inflammatory diathesis by assessing signs of immune activation and vasculopathy during a psychiatric symptom exacerbation (flare), estimating the risk of developing arthritis and other autoimmune diseases, and characterising subtypes of arthritis.
Design, Setting, and Participants
This retrospective cohort study used longitudinal clinical data on 193 consecutive patients with PANS followed up within the Stanford Immune Behavioural Health Clinic from September 1, 2012, to December 31, 2021.
Main Outcomes and Measures
Medical records were reviewed, and a predefined set of immune markers that were measured during a flare and the features and imaging findings of arthritis and other autoimmune diseases were collected. Immune activation markers included (1) autoimmunity signs (antinuclear antibody, antihistone antibody, antithyroglobulin antibody, C1q binding assay, and complement levels [C3 and C4]); (2) immune dysregulation or inflammation signs (leukopenia, thrombocytosis, C-reactive protein, and erythrocyte sedimentation rate); and (3) vasculopathy signs (livedo reticularis, periungual redness and swelling, abnormally prominent onychodermal band, palatal petechiae, high von Willebrand factor antigen, and high d-dimer). Last, the cumulative risk of developing arthritis and autoimmune diseases was estimated using product limit (Kaplan-Meier) survival probability.
Results
The study included data from 193 children (112 boys [58.0%]) who had PANS at a mean (SD) age of 7.5 (3.5) years. They were followed up for a mean (SD) of 4.0 (2.1) years. Among those tested for immune activation markers, 54.2% (97 of 179) had nonspecific markers of autoimmunity, 12.0% (22 of 184) had nonspecific signs of immune dysregulation or inflammation, and 35.8% (69 of 193) had signs of vasculopathy. By 14, the estimated cumulative incidence of arthritis was 28.3% (95% CI, 20.8%-36.3%), and the estimated cumulative incidence of another autoimmune disease was 7.5% (95% CI, 4.0%-12.4%). Novel findings in the subgroup with arthritis include joint capsule thickening (55.0% [22 of 40]), distal interphalangeal joint tenderness (81.8% [45 of 55]), and spinous process tenderness (80.0% [44 of 55]). Among the 55 patients with arthritis, the most common subtypes of arthritis included enthesitis-related arthritis (37 [67.3%]), spondyloarthritis (27 [49.1%]), and psoriatic arthritis (10 [18.2%]).
Conclusions and Relevance
This study found that patients with PANS show signs of immune activation and vasculopathy during psychiatric symptom flares and have an increased risk of developing arthritis and other autoimmune diseases compared with the general paediatric population. The most common arthritis subtype was enthesitis-related arthritis. These findings suggest that PANS may be part of a multisystem inflammatory condition rather than an isolated psychiatric or neuro-inflammatory disorder.
JAMA Network comment – Strep Throat and the Backstory for PANS and PANDAS (Open access)
Medpage Today article – Researchers Try to Better Understand PANS/PANDAS (Open access)
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