PANDAS and PANS revisited

Maybe one day I will see one.

By 2015, when Adam was 8, Elliott began to fear she might have to have him hospitalized. She took him for a full psychological evaluation with Rebecca Daily, an autism specialist at the University of Oklahoma. During the visit, Elliott mentioned that Adam’s problems had all started when he was a toddler, around the time he had had his tonsils and adenoids removed. Doctors had recommended the surgery because he had had so many bouts of strep throat.

“What did you say?” Daily asked.

Elliott repeated what she had said.

She remembers Daily then saying: “This is not autism, this is not ADHD. This is a disease called PANDAS.”

Elliott had never heard of PANDAS, short for ‘pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.’ But the diagnosis had been gaining traction over the previous two decades. In 1998, Susan Swedo, then a pediatrician at the U.S. National Institutes of Health (NIH), first proposed PANDAS to explain an apparent association between strep throat, obsessive-compulsive disorder (OCD) and tic disorders such as Tourette syndrome. By Swedo’s estimate, the condition affects up to 1 in 200 children, but many experts contest that figure — and even the condition’s very existence.

Pediatric neurologists point out that Tourette syndrome and OCD are highly heritable; if strep plays a role in these conditions at all, it is extraordinarily rare. Strep, by contrast, is common. In one study that followed 814 children for 12 weeks, for example, about half of the children had ongoing strep infections, and they did not show more obsessive-compulsive behaviors or tics than the other children.

Still, PANDAS has attracted a vocal band of proponents who have proposed it as a catchall for a wide range of mental health issues sometimes lumped under the broader term ‘autoimmune encephalopathy.’ The list of purported triggers has grown from strep to include Lyme disease, mononucleosis and herpes. And the range of possible outcomes has expanded to encompass ADHD, anorexia nervosa and autism. The boundaries between these diagnoses can be subjective, and some clinicians and parents are quick to attribute obsessive-compulsive behavior to PANDAS, even when it may stem from autism, OCD or something else. “There’s going to be diagnostic confusion whether a child has a late presentation of autism or if they have PANDAS,” Swedo says.

Daily recommended that Adam take a test developed by a colleague of hers, microbiologist Madeleine Cunningham. Oklahoma-based Moleculera Labs, which Cunningham co-founded, markets the $925 test — called the ‘Cunningham Panel’ — for children who are not responding to treatments for psychiatric conditions and who may instead have “a treatable autoimmune disorder.” One brochure reads: “Could an infection be causing your child’s symptoms?”

Whether they pursue the test or not, parents who suspect their child has PANDAS often end up seeking expensive, unproven and potentially dangerous treatments — including, in rare cases, rituximab, an immunosuppressant typically used for cancer treatment and organ transplants that has serious, sometimes deadly, side effects. Medical quacks and profiteers have thrived, largely unchecked in a marketplace that intersects with the outer fringes of the autism and chronic Lyme communities. One Oklahoma company, for instance, markets donkey milk as a PANDAS treatment. Most parents end up paying out of pocket, but five states have passed laws mandating insurance coverage for treatment of the condition.

The condition’s rising popularity notwithstanding, several experts say the way it is being diagnosed and treated is worrisome. “Allow me to be considered a naysayer,” says Edward Kaplan, an expert in streptococcal infections at the University of Minnesota in Minneapolis. He says there may be a neurological trigger for the behavioral changes in some children diagnosed with PANDAS, but the link to strep is tenuous at best. “This disease is diagnosed by all kinds of people more frequently than perhaps it should be.”…

Swedo then inverted her approach. Rather than seeking out children with rheumatic fever, she began studying children with OCD and Tourette syndrome, and swabbing their throats for evidence of a strep infection. She often found it — which is not surprising because it is a common infection, and many children also carry the bacteria without getting sick. What was surprising, Swedo says, was what happened when she started treating those children.

She recalls one child who refused to swallow his spit, preferring, instead, to stockpile it. “He had three cups under his bed,” she says. When she treated him with penicillin, she says, “he responded beautifully; his obsessive-compulsive symptoms disappeared.” He then had another strep infection, and the OCD-like behavior “came roaring back.” In another child, she tried ‘plasmapheresis,’ a technique to separate the child’s blood cells from the plasma and strip out the germ-fighting antibodies circulating in his system. She says that led to an 80 percent decrease in the boy’s OCD traits, according to his parents…

It was PANDAS that would become Swedo’s legacy. In 1998, Swedo proposed five criteria to diagnose PANDAS: the presence of OCD or a tic disorder, sudden onset prior to puberty, a waxing and waning pattern of trait severity, an association between strep infections and behavioral traits, and neurological abnormalities such as jerking movements or problems with coordination. Despite the clear, testable criteria she laid out, the definition of PANDAS proved elastic in the hands of practitioners. By 2008, one study had found that only 39 percent of children diagnosed with PANDAS actually fit Swedo’s original definition. So many children were diagnosed, in fact, that Stanford University’s multidisciplinary PANDAS clinic — the first of its kind when it opened in 2012 — sees children from within only a seven-county area and only if they agree to participate in research.

Given the surge of interest, the NIH launched a $3 million multicenter study — the largest and most rigorous analysis of the condition.[1] The researchers followed 71 children who met PANDAS diagnostic criteria over two years and compared them with children who had traits of Tourette syndrome or OCD but not PANDAS. Two landmark studies, published in 2008 and 2011, found that in 91 percent of all PANDAS cases, there was no association between the timing of strep infections or presence of strep antibodies and flare-ups of OCD or tics. Even though children with PANDAS were more likely to receive antibiotics than the other children were, the researchers could detect no difference in the number of flare-ups the children experienced…

Cunningham tested whether these five molecules might serve as diagnostic markers for PANDAS and concluded that they did. But in 2008, independent studies at Johns Hopkins University in Baltimore, Maryland, raised doubts about the utility of Cunningham’s biological markers and the link between infection and PANDAS flare-ups.

That did not keep Cunningham’s team from the patent office: In 2011, Cunningham and Craig Shimasaki, a molecular biologist and entrepreneur, founded Moleculera Labs to commercialize the test Cunningham had developed. Their website says that a single elevated enzyme “may indicate a clinically significant autoimmune condition.” This claim clashes with published results showing similar levels of the enzyme in people with and without PANDAS. Moleculera has reported that autistic children may also receive a positive result, raising further questions about the utility of the test…

In one 2017 study, the Cunningham Panel did not distinguish 20 people with psychiatric conditions who met the formal criteria for PANDAS or PANS from 33 who did not.[2[ Susanne Bejerot, professor of psychiatry at Örebro University in Sweden, who led the study, was so disturbed by the findings that she recruited 21 controls — including a fellow doctor with no history of mental illness — to take the test. She found that 86 percent tested positive for at least one of the five markers on the Cunningham Panel. “Parents are very happy about the Cunningham Panel because they always get positive results,” Bejerot says. “That means they can show it to a clinician and get antibiotics or other treatments.”…

[Donald] Gilbert studied philosophy before he became a doctor. He gives lectures on PANDAS that sound more like epistemology than medicine, as he explores the role of inference and the nature of causality. “I’m a skeptic by nature,” he says.

In August 2018, Gilbert gave a talk for primary care physicians with the relatively staid title “PANDAS and PANS: A clinician’s guide to management.” In it, he challenged the anecdotal evidence PANDAS supporters frequently cite. He also recommended that, unless OCD traits make it impossible for a child to attend school, clinicians should not run any tests, offer any treatments or provide any neurology referrals. In his slides, he wrote: “Inoculate the family with education so they do not seek out a PANDAS/PANS clinic.”

After the Cincinnati Children’s Hospital posted a video of the talk online, the PANDAS Network, a nonprofit advocacy organization that is listed as one of the National Institute of Mental Health’s Outreach Partners, shared it on Facebook. All hell broke loose. “Move over you foolish man,” read a comment from the PANDAS Network’s account. “Step away from the podium.”

“His swipes at Dr. Swedo and Cunningham … are so incredibly rude and flat-out unprofessional,” one commenter wrote.

“This man needs to be stopped,” wrote another.

Within a week, the group had issued a “call to action,” directing its members to file complaints against Gilbert with the Ohio State Medical Board and the Accreditation Council for Continuing Medical Education. “[Dr. Gilbert] mocked the disorder, disparaged researchers, misled attendees, encouraged physicians to commit medical malpractice, and generally enjoyed a jolly good time laughing along with his colleagues at desperate parents,” attorney Beth Maloney wrote in a letter to his employer. “The general medical bigotry that was on full display caused me to wonder whether your hospital will next try to take PANDAS children from parents who disagree with its doctors.”

Gilbert says he was upset by the attacks but chose to ignore them at first. When he attended a professional conference a few months later, however, the organizers left his name off the program and advised him to register at the hotel under a false name for his own safety.  While he was there, he says, Swedo, who retired from the NIH last year and now serves as chief science officer for the PANDAS Physicians Network, asked to meet him.

When they met in the conference hotel, Swedo handed him printouts of his slides along with her handwritten responses. Gilbert disagreed with her about the science but says he saw that she wanted him to recognize the rigor in her own work. Swedo says she remains deeply offended that Gilbert compared her to a quack. “I had grounds to sue him, but I chose not to,” she says. She says she tries to warn parents about snake-oil salesmen and shuns healthcare providers she believes are over-diagnosing PANDAS. She lays blame for the explosion in questionable fringe therapies on the PANDAS naysayers such as Gilbert. “The controversy is responsible for the overtreatment of these kids,” Swedo says. “Mainstream medicine has failed to deliver recognition of suffering and a promise that we are going to find out what is happening.”

https://www.spectrumnews.org/features/deep-dive/how-a-controversial-condition-called-pandas-is-gaining-ground-on-autism/

[1] Leckman JF, King RA, Gilbert DL, Coffey BJ, Singer HS, Dure LS 4th, Grantz H, Katsovich L, Lin H, Lombroso PJ, Kawikova I, Johnson DR, Kurlan RM, Kaplan EL. Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry. 2011 Feb;50(2):108-118.

[2] Hesselmark E, Bejerot S. Biomarkers for diagnosis of Pediatric Acute Neuropsychiatric Syndrome (PANS) - Sensitivity and specificity of the Cunningham Panel. J Neuroimmunol. 2017 Nov 15;312:31-37.

See:  https://childnervoussystem.blogspot.com/2019/09/a-pandas-tale.html
https://childnervoussystem.blogspot.com/2019/04/pandas-commentary.html
https://childnervoussystem.blogspot.com/2019/02/pans-and-pandas.html
https://childnervoussystem.blogspot.com/2018/07/pandas-stories.html
https://childnervoussystem.blogspot.com/2018/01/a-rare-disease-or-no-disease-at-all.html
http://childnervoussystem.blogspot.com/2016/10/a-pandas-or-pans-story.html
 http://childnervoussystem.blogspot.com/2015/06/maybe-one-day-ill-see-one.html