Editor’s Note: *The names of family members in this story have been changed to protect their privacy.
*Joan’s son, *Sam, was the easiest of her three kids – a good eater, quiet and snuggly. But when he was 3, everything changed. Like the flip of a switch, Sam’s behavior spun out of control. Suddenly, he was anything but easy.
Almost overnight, he became aggressive, throwing chairs, kicking filing cabinets and pushing his preschool classmates. He had extreme separation anxiety and lost the ability to sleep alone. Later, Joan and her husband, who live in O’Fallon, Mo., learned Sam was also experiencing hallucinations that would scare him into hiding under a table at school.
Joan feared a brain tumor, which seemed like the only way to explain Sam’s sudden about-face in demeanor. Her extended family thought he was possessed.
Doctors diagnosed him with a litany of illnesses: attention deficit hyperactivity disorder, Asperger syndrome, oppositional defiant disorder, compulsions and tic disorder.
But Joan, a pediatric physical therapist, knew these diagnoses didn’t fully describe what was wrong with her son. At the height of his illness around 8, Sam was battling intense suicidal thoughts and putting his fists through walls.
“Our family was falling apart,” Joan said.
Eventually, she became convinced her son suffered from a psychiatric disorder so rare and controversial that not all doctors even agree it exists. Called PANDAS – short for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections – the puzzling illness is characterized by a sudden onset of obsessive-compulsive and tic behaviors, such as scary, intrusive thoughts and unstoppable grunting.
But its proposed trigger is even more perplexing. Doctors who study this condition believe it may be brought on by a strep infection, the kind known for causing millions of sore throats each year. In some children, this painfully common infection may provoke an alarming symptom – mental illness.
Strep causes inflammation and activates the immune system. But in the case of PANDAS, the body mistakes its own healthy cells for invading bacteria. Biological attacks mount against the brain. Neurons misfire. And behavior comes unhinged.
But not every child who gets strep winds up in the throes of this illness – and it’s not clear why. Contention over whether PANDAS is real and its supposed link to strep remains heated.
One thing is clear: We understand frustratingly little about how the immune system affects the brain. But the study of this condition may help to shed light on more common neurological disorders, including depression, Alzheimer’s disease and autism. If some forms of mental illness can be caught like a cold or the flu, then more effective treatment or even prevention becomes a real possibility.
A sudden onset
The short history of PANDAS is ruled by two warring camps – the believers and the skeptics. Academic meetings and the research literature have aired a contentious debate about this disorder, its causes and whether it exists at all. Both sides remain stanch in their claims.
Dr. Susan Swedo, the pediatrician who originally identified the disorder, leads the believers.
In the 1980s, Swedo began investigating Sydenham’s chorea, in which patients display involuntary, jerky dance-like movements. This disorder accompanies rheumatic fever, an inflammatory disease that develops when a Group A streptococcal infection – commonly referred to as strep – goes untreated.
Swedo, who is now chief of the Pediatrics & Developmental Neuroscience Branch at the National Institute of Mental Health in Bethesda, Md., noticed that about two-thirds of patients with Sydenham’s chorea also had OCD-like behaviors and emotional disturbances.
And, in most cases, these symptoms came on in a frighteningly abrupt manner.
“They were fine one day, and then the next day were doing all of these odd behaviors and having worrisome thoughts in their head,” she said.
Her interest piqued, Swedo looked for this pattern in children who had OCD without Sydenham’s chorea. She examined over a hundred children and found that most developed OCD symptoms in the typical gradual manner. But a quarter of them had a sudden onset. They also displayed abnormal movements, such as wiggling fingers as if they were playing the piano.
The similarity of these other symptoms to those of Sydenham’s chorea led Swedo to explore a link between strep infections and acute-onset OCD. She found 50 children with an abrupt onset of symptoms that seemed to worsen with strep infections and then later remit. In 1998, she published these results, coining the name PANDAS.
Alongside obsessive-compulsive symptoms and tics, Swedo described other characteristics of the disorder, such as anxiety and depression. Later studies showed some of the children had problems with urinary control and deteriorating handwriting. Most patients seemed to develop a chronic condition, in which new strep infections exacerbated tics and obsessive behaviors. Reports started to show that these symptoms abated with antibiotic treatment.
“Early on it was met with quite a bit of enthusiasm and excitement, and then time passed, the critics emerged and the controversy developed,” she said.
Over the next decade, editorials questioning the link between strep and PANDAS hit the literature. Swedo was publicly berated and accused of falsifying data.
Disagreement over the condition trickled down to primary care physicians and pediatricians. Many avoid discussing it as a possible diagnosis because it’s too controversial. What’s sad, according to Swedo, is the effect this contention has had on families.
This was the case for Joan, whose son was treated by a pediatrician and two neurologists for years before she even heard about PANDAS. At a Target in 2011, Joan ran into an old friend whose son happened to be experiencing the same problems as Sam. After late nights of Googling, Joan was convinced PANDAS was the source of her son’s suffering. She had Sam tested with a standard strep swab – even though he was without a fever or sore throat – and it was positive.
But when she called every pediatric neurologist in St. Louis, no one would agree to evaluate Sam. Despite the family’s proximity to one of the best children’s hospitals for neurology in the country, Sam was finally diagnosed by Miroslav Kovacevic, a Chicago-area pediatrician who acknowledges and treats the disorder.
Mild strep infections in the throat and on the skin number in the millions each year in the U.S., yet the estimated prevalence of PANDAS is a tiny fraction of that. This leads some doctors and scientists to question whether strep triggers the condition – or whether PANDAS even exists.
Harvey Singer, one of the leading skeptics, is not yet convinced.
“The bottom line is that there are all of these questions out there that need to be addressed,” said Singer, a neurology and pediatrics professor who studies Tourette syndrome and other movement disorders at the Johns Hopkins University School of Medicine in Baltimore.
For one, a single positive throat culture for strep does not a PANDAS patient make, he said. Many studies – including Swedo’s seminal 1998 study – base the connection between strep and PANDAS symptoms on individual throat cultures or blood tests. But when he and his colleagues tested children for strep each month for two years, they found no systematic association between the infections and periods of worsened symptoms. In addition, up to a quarter of school-age kids test positive for strep during winter months, but most of them carry the infection without experiencing a serious illness.
“Unfortunately, parents like to have a simple explanation,” he said. “Sometimes what’s simplest is not necessarily correct.” Singer stresses the importance of considering other possible explanations of symptoms – such as Sydenham’s chorea – before jumping to the possibility of PANDAS.
But what seems to be less controversial is the idea that children may suffer from an abrupt onset of OCD-type symptoms. This was the original focus of Swedo’s studies, and in 2012, she and her colleagues expanded their concept to PANS, or Pediatric Acute-Onset Neuropsychiatric Syndrome, which does not require a strep infection linked with symptoms.
To be diagnosed with PANS, children must display neuropsychiatric behaviors, such as anxiety or depression, in addition to an acute onset. And similar conditions, like Syndenham’s chorea or Tourette syndrome, must be ruled out first. Prevalence estimates for this broader diagnosis are still unclear, but about 75 percent of PANS patients do have a link to strep, according to Swedo.
With a widened lens, researchers are studying additional potential infectious triggers, such as respiratory infections, flu and Lyme disease.
Still, the field as a whole is very new, said Dr. Michael Cooperstock, another believer and director of the pediatric infectious diseases division of the University of Missouri School of Medicine.
“As the field is emerging, the facts aren’t all there, and so as long as the picture isn’t scientifically completely filled in, there’s room for disagreement,” he said. Cooperstock has been studying infection-linked neuropsychiatric disorders since a girl with Sydenham’s chorea came to his clinic three years ago.
He’s part of the PANS Collaborative Consortium, a group of doctors and scientists who are working to unravel the mystery of this illness. In 2013, they gathered at Stanford University to discuss clinical guidelines for diagnosis and treatment. Hoping to better inform the medical and scientific community, they published a statement in February outlining their conclusions.
For Cooperstock, the patients solidify his resolve to understand the condition and increase awareness. He has now seen more than 70 patients, including five from Boone County. But he has more referrals than he can handle – pouring in not only from Missouri but also Iowa, Arkansas and even California.
“When a mother looks you in the eye and says, ‘On that day I lost my daughter, and I really haven’t seen her quite back again since, and it’s now a year later,’ you start to become a believer,” he said.
If an infection is the culprit in this condition, the prime accessory is a misdirected immune response. As the body counters an infection, it triggers the production of antibodies – Y-shaped proteins that tag invading particles for attack by the immune system. Sitting at the tip of each arm of the antibodies are structures designed to recognize and bind specific foreign substances, like a lock matches a key.
But sometimes the antibodies mistakenly recognize keys on both foreign substances and healthy cells. When this happens, a person’s immune system turns on the body it’s trying to protect and starts attacking healthy tissue. This process – known as autoimmunity – underlies conditions such as lupus, Type I diabetes and multiple sclerosis. It’s also commonly linked with overactive inflammation in the body.
In the case of PANS, the body may produce overzealous antibodies that target brain cells in addition to strep bacteria or other infections. These overactive antibodies bind at least four targets in the brain, according to Madeleine Cunningham, professor of microbiology and immunology at the University of Oklahoma Health Sciences Center.
Two of the targets Cunningham studies are the proteins in neurons that respond to dopamine, a chemical that activates the reward and pleasure centers of the brain. Dopamine also plays an important role in an area in the middle of the brain called the basal ganglia, which guides our voluntary movements like the gas and brake pedals on a car. Some signals from the basal ganglia press the gas, moving our limbs. Others hit the brakes, halting motion.
In PANS patients, antibodies target the basal ganglia, causing too much dopamine to be released. Motor signals go haywire. This may lead to the compulsions and tics many patients display.
Cunningham has developed a blood test – dubbed the Cunningham Panel – for the antibodies that target brain cells. Elevated blood levels of any these antibodies signal inflammation and potentially an autoimmune condition. If hallmark symptoms such as obsessive-compulsive behaviors are also present, the diagnosis may be PANS. With this information in hand, doctors can consider immunological treatment options, such as plasmapheresis. In this procedure, a patient’s harmful antibodies are filtered from the blood and exchanged with healthy donor plasma.
But at $925 a pop, the panel is expensive, and it’s available only from Moleculera Labs, of which Cunningham is a co-founder and chief scientific officer. Insurance companies may pick up some of the tab, but families must mail in almost half the cost before they receive the test materials. Still, the company has collected around 2,000 samples from patients in two years.
Cunningham is collaborating with Cooperstock to organize a database of patients and their test results. But the connection between combinations of antibodies and symptoms is likely complex, Cooperstock said.
A new era
PANS research is just getting its footing, according to Cooperstock. Everything is changing. Everything is new.
“We’re just at the dawn of a new era,” he said. In February, the Journal of Child and Adolescent Psychopharmacology ran a special issue on PANS. In many ways this collection of articles outlines the future of the field.
Treatment remains one of the biggest challenges. It’s not fair to ask families to wait while their children suffer, Swedo said. So far, she thinks, antibiotics show the most promise. This treatment has been supported anecdotally since the disorder’s discovery, but preliminary empirical evidence is now coming in.
Using antibiotics as a preventative measure may also be feasible. Reducing the chance of getting strep or other infections would, presumably, hold harmful antibodies at bay. But some of Swedo’s early studies don’t definitively support this approach. And the risk of inducing antibiotic resistance is a big concern.
Swedo is investigating a more drastic option for severely affected children, the ones who stop eating or try to jump out of moving cars. The treatment involves infusing pooled antibodies extracted from about 1,000 donors to hit the reset button on a malfunctioning immune system. This process is called high-dose intravenous immunoglobulin, or IVIG. In an initial study, Swedo showed that IVIG improved symptoms in patients with PANDAS, and she’s analyzing the results from a recently completed larger clinical trial.
But IVIG is not cheap, costing anywhere from $4,000 at wholesale price to $15,000 at clinics. And there’s no guarantee that it will work. Sam underwent the treatment in 2011 and saw some improvements, but it wasn’t until he cut gluten and dairy from his diet and discontinued all prescription drugs that he really started making strides, his mother said. This further supports a role of inflammation in PANS. Sam, now 13, is a typical teenager, Joan said. He’s getting almost straight A’s and just started football. His tics are completely gone.
Another unconquered frontier is the susceptibility question – why do some children get PANS and others don’t? Cunningham and other researchers think a genetic predisposition is likely. Specifically, a class of genes that help regulate the immune system may be disrupted.
Many patients also have a family history of OCD, tics or even rheumatic fever. Sam’s grandmother had Sydenham’s chorea. And his 9-year-old brother, *Andy, has a milder form of PANS. His symptoms – facial tics and occasional bouts of anxiety – are also under control.
As answers about PANS emerge, the fields of immunology, neuroscience and psychiatry at large stand to gain. Research on this condition and others like it is fortifying a greater understanding of the tangled link between the immune system and mental health. As some scientists suspect, autoimmunity and inflammation could be at the root of many neuropsychiatric disorders.
A well-known example is anti-NMDA receptor encephalitis, a condition made famous by young journalist Susannah Cahalan’s bestselling account of her illness, “Brain on Fire.” Like PANS, it is driven by a misdirected immune response attacking a protein in the brain. But instead of OCD, patients experience extreme psychosis and seizures. Scientists have been able to pinpoint the exact neuronal target that leads to this terrifying illness.
Cunningham is beginning to explore whether antibodies can also target brain receptors activated by serotonin – a neurochemical that helps regulate mood, sleep and appetite. This work may help explain why some PANS patients experience depression. And other researchers are studying depression with the lens of inflammation.
“The brain is the last frontier, and we and other researchers are going to figure out that many neuropsychiatric diseases are caused by inflammation,” she said.
Nothing is off the table, according to Cooperstock. Complex conditions such as post-treatment Lyme disease syndrome, anxiety, ADHD and even anorexia all become open territory for investigation, he said.
Evidence linking immunological factors to several other neurological conditions is starting to pile up. Psychosis in children may be immune-related, according to a study published in March. A recent study also showed malfunctioning immune cells in a mouse model of Alzheimer’s disease. And researchers at the University of California, Davis are examining how antibodies in some pregnant women can cross the placenta and attack fetal brains. This prenatal disruption may increase the risk of some forms of autism.
These possibilities remind Swedo of her initial work in this area almost 30 years ago. Just as before, there are lots of ideas to explore and new questions to ask.
“We’re just in the sort of exciting early stages where anything is possible,” she said. “It’s just very wide open.”
8 thoughts on “Infected mind: A rare autoimmune condition spurs controversy, forges new frontiers”
This was one of the best articles on this topic. Informative but not salacious. My child has this illness and we see Dr. Cooperstock. It was awesome to see him quoted. I am thankful to the writer that did such a thorough explanation of this nightmare that those of us who know this illness live in.
Yes it was a great article. My grandson (10) has been seeing Dr. Cooperstock for over a year now, and we are seeing much better results. The anti-biotic treatment he is on is working very well. We only see a flare up maybe once or twice a month. He has never had the tics with his P.A.N.D.A.S.
I am 46 years old, with serious mental illness symptoms that followed an abusive relationship with a malignant narcissist. I also had encephalitis in my late 20’s. What followed is what I would describe as nearly verbatim what I read above.
Good morning Rachel,
In your excellent article, https://unearthedmag.wordpress.com/2015/05/07/infected-mind-a-rare-autoimmune-condition-spurs-controversy-forges-new-frontiers/comment-page-1/ the statement is made regarding the Cunningham Panel as follows:
“But at $925 a pop, the panel is expensive, and it’s available only from Moleculera Labs, of which Cunningham is a co-founder and chief scientific officer. Insurance companies may pick up some of the tab, but families must mail in almost half the cost before they receive the test materials.”
We felt that it was important for you to have the following information. The cost of our tests includes 5 tests and the initial deposit does not cover our costs of doing the test. Moleculera was founded as a way to help parents who wanted to have their children tested when Dr. Cunningham’s study concluded. Parents continued to ask for testing that was no longer available to them and Dr. Cunningham received calls from around the world on a daily basis.
It is true that we are the only lab in the world that does this test. We are having increasing effectiveness obtaining insurance reimbursement for our patients as we promote and disseminate peer reviewed journal articles such as the ones attached to this email. Regarding the expense of the tests, we realize that it is costly. That is why we hope that parents will have their children tested as soon as possible following the onset of symptoms as parents exhaust their financial and emotional resources going to many doctors and pursuing ineffective and sometimes harmful treatments when their child actually needs simple antibiotic therapy. We hope that parents will use the test as a first course of action rather than a last resort when resources are already depleted. That way they get their answers earlier when treatment is simpler, more cost effective and less invasive.
Please call us if you would like more information or if you would like to have an interview with our CEO, Dr. Craig Shimasaki, or Dr. Cunningham. We are always here to help.
Amy Cross, RN
Amy Cross, RN MS
Medical Relations Coordinator
Moleculera Labs, Inc
Link for Consensus Document: http://online.liebertpub.com/doi/abs/10.1089/cap.2014.0084
Link for Antineuronal Antibodies Document: http://online.liebertpub.com/doi/abs/10.1089/cap.2014.0048
I heard that children can get PANDAS from having chronic Lyme disease and possible co-infections.
I am the parent of a child who is waiting for a PANDAS evaluation appointment. Most informative article I have come across so far. A friend with chronic Lyme and Bartonella infections recommended it. I’m passing the article to my husband to read right now. thanks for covering this topic so well.
My son just tested positive on four of the tests in the panel out of 5 tests. He had both undiagnosed strep and diagnosed lyme at the age of 3. We took him to many doctors over many years but it wasn’t until an ND recognized a rash on his back as Bartonella did we pursue the possibility of PANS. He is now 16 and has OCD, Anxiety, ADD, Depression. His OCD presents as constant ear cleaning, compulsive eating of sugar followed by no eating, video game obsession and coveting same items of different colors. His anxiety was severe from ages 7-10 and manifested as separation anxiety but has subsided significantly with prescription medications. His symptoms are apparently classic but went undiagnosed for 12 years after visits to PCP, endocrinologist, immunologist, dermatologist, psychiatrist, psychotherapist, neurologist. My son has lost his childhood to this illness. I’m grateful for the opportunity to treat with purpose now and my only regret is that there are so few PANS literate doctors and that finding good care will be difficult.
Thank you for this poignant and validating article.
My son is 38 year old now. Cunninham panel test is done all of the results way high. IVIG was given in subq, but much improvement. He got OCD, Epilepsy and behavioral issues. I wonder there is any Doctor in NY, CT,NJ to continue the treatment.