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Pediatric acute-onset neuropsychiatric syndrome (PANS) -- along with the related pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) -- may be a controversial diagnosis, but a new study attempts to better characterize it.

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 University in Palo Alto, California, and colleagues, writing in .

They noted a heightened risk of arthritis in their cohort and concluded that PANS "may be part of a multisystem inflammatory condition rather than an isolated psychiatric or neuroinflammatory disorder."

The term PANDAS was coined in 1998 when a team at the National Institute of Mental Health described 50 kids 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 .

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 behavioral problems, and emotional imbalance.

Yet few physicians are trained to recognize the condition, according to Aravindhan Veerapandiyan, MD, a pediatric neurologist at Arkansas Children's Hospital in Little Rock who co-directs its Childhood Post-infectious Autoimmune Encephalopathy Center 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 乌鸦传媒. Some of the reasons for that skepticism include "a lot of not-so-evidence-based practice out there" 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 kids were followed for a mean of 4 years. More than half were boys (58%) and 83% were white.

They found that 54% had nonspecific 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, characterized 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 that I've made in our practice, which is that there are a relatively large number of children in this population who have a very particular kind of arthritis that they develop," Whelan told 乌鸦传媒.

He said he's had success treating kids with PANS/PANDAS based on this model: "[T]his is something that 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 behavioral issues."

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 where the patient population was drawn from, is a rheumatologist, "so the patients that are seen in the clinic, they are most likely going to have some sort of rheumatological problems."

Frankovich emphasized 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 乌鸦传媒.

Once her patients are treated with immunomodulators, she added, they can begin to tolerate other treatments that then seem to work better, like cognitive behavioral 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," he said, "it's kind of fallen to the rheumatologist, because we're really the consultants of last resort."

Parents and patients with PANS/PANDAS often typified by skepticism, unfamiliarity, and difficulty diagnosing what may look like OCD or bipolar disorder. Some major pediatric hospitals that they will not see PANS/PANDAS patients. Whelan described families rattled by the sudden changes in their child's behavior and caregivers who had to halt their careers to look after a child who can no longer attend school.

Veerapandiyan, who usually deploys antibiotics, anti-inflammatories, and steroids to treat the condition, said immunosuppressants have also shown promise, anecdotally. He's also leading a of intravenous immunoglobulin for the condition.

More research on PANS/PANDAS is needed, he said, and there should be "more efforts to actually create awareness and education of more appropriate information for families and providers on this."

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