In 1994, Susan Swedo, a researcher at the National Institute of Mental Health (NIMH) in Bethesda, Maryland, had a hunch that there might be an immunological explanation for obsessive-compulsive disorder. As a model, she was studying a phenomenon known as Sydenham’s chorea, or St. Vitus’ dance.
First described centuries ago, Sydenham’s chorea is a rare manifestation of rheumatic fever that affects children almost exclusively. It is a disconcerting, unmistakable illness to witness. Children are overcome by rapid, uncontrollable jerking of the hands, feet, and face, contorting their bodies in a distorted, disturbing “dance.”
Sydenham’s chorea is caused by molecular mimicry gone wrong. Molecular mimicry generally works like a wolf in sheep’s clothing. Streptococcus bacilli have thrived through the eons by cloaking themselves in proteins that resemble their host’s own cells. Disguised, it evades the immune system just long enough to establish an infection.
But sometimes this tactic sets off an unfortunate chain of events. When the immune system mounts its counterattack, it wipes out the wolf and the sheepskin it’s wearing. In classic rheumatic fever, the antibodies mistake the lining of the heart for strep bacilli. In Sydenham’s, the basal ganglia have a particularly fleece-y look. That, in turn, helps explain an afflicted child’s odd motions. The basal ganglia are walnut sized areas of the brain that serve as a sort of traffic light, signaling the muscles in the proper order to make voluntary movements.
When the basal ganglia are damaged or attacked, the disruption can be severe—as though the traffic light was permanently stuck on green. Everything from Parkinson’s and cerebral palsy to attention deficit hyperactivity disorder (ADHD) have been connected to damaged basal ganglia. “The basal ganglia are the gatekeeper between the brain stem and motor function and the upper brain. They say ‘stop, go, stop, go,’ ” says Swedo. “When they don’t work right, think of the gate as stuck open in certain areas—it’s a failure to inhibit the motor impulse in blinking or twitching.”
Just as puzzling are kids who don’t get PANDAS. That’s led to more than a decade of debate over whether it exists at all.
As Swedo collected case histories of children with OCD, Swedo began to notice remarkable parallels with Sydenhams.’ Most cases of OCD come on slowly, with tics accumulating and intensifying over months and years. But in about a quarter of the childhood-onset OCD cases Swedo looked at, the compulsive behavior came on like a light switch, going from normal to severe overnight. It was often accompanied by tics, like throat clearing and grunting; severe separation anxiety; bed-wetting; and changes in handwriting as fine motor control broke down.
Like rheumatic fever and Sydenham’s chorea, Swedo found, children whose OCD, tics, separation anxiety, and other symptoms came on suddenly often had strep infections not long before their first symptoms appeared. If strep could cause Sydenham’s, she wondered, could it also be affecting kids’ thoughts and behavior? In a 1998 paper, she proposed a link between strep, OCD, and the other symptoms she was seeing, calling the phenomenon “pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections,” or PANDAS.
Isak McCune’s experience is typical of PANDAS. In classic autoimmune diseases like Type 1 diabetes or lupus, the immune system spontaneously mistakes cells in the body for invaders. In PANDAS and Sydenham’s chorea, Swedo says, the attack is set off by an actual infection. As long as the immune system senses strep in the body, it produces antibodies tailored to fight the bacteria.
In people with PANDAS, though, the antibodies slip through the blood-brain barrier to attack similar-looking proteins on the cells of the basal ganglia. “The antibodies are somewhat sloppy; they cross-react with other proteins and chemicals,” says Hornig. “That can lead to changes in behavior or the brain.”
When it comes to treatment, the presence of strep antibodies in the blood of children with OCD is a positive sign. Remove the infection, and the crippling behaviors often go away, too. Once their bodies stand down from the fight against strep, the “cross-reactive” attacks on the basal ganglia seem to stop as well.
Artificially dampening the immune system seems to work in a similar way. Tricia Lord, a California parent whose son Kirk was treated for PANDAS in 2011 with steroids, an immunosuppressant, says she saw improvement within hours. “He was back to what he was before all this happened,” Lord says. “I couldn’t believe it. He seemed better than 100 percent.” (Kirk relapsed after a month, and doctors tried intravenous immunoglobulin, a procedure, designed to regulate the immune system, that infuses patients with antibodies extracted from healthy donors.1 He’s now off all medications and performing above his grade level.)
Much remains mysterious, Swedo says, about the symptoms of PANDAS. One of her early PANDAS cases was a 12-year-old girl convinced she caught rabies from an unopened hypodermic needle she found in her pediatrician’s parking lot. At the age of 5, Kirk Lord developed severe separation anxiety almost overnight, and sunk into a listless state his parents dubbed “the Fog.” Other kids afflicted with PANDAS hear voices or experience “Alice in Wonderland” syndrome, wildly distorted perceptions of size and distance some liken to waking nightmares. “Why is it rabies, or AIDS, or spearmint gum? Some are so random you scratch your head,” Swedo says.
Just as puzzling are the kids who don’t get PANDAS. Strep can be dangerous, but it’s a common part of childhood. The average grade school student comes down with strep twice a year, according to the National Institutes of Health. Yet 1,999 out of 2,000 don’t develop PANDAS. And Swedo estimates that PANDAS accounts for just 10 or 20 percent of all pediatric-onset OCD cases.
That’s led to more than a decade of debate over whether PANDAS exists at all. When Swedo and her colleagues first published their PANDAS results, there was a backlash from Harvey Singer, a professor of neurology and pediatrics at Johns Hopkins University, and Tourette’s researchers, who questioned the idea that a common childhood illness caused tics and OCD. In an influential 2011 Journal of Pediatrics paper, Singer called the evidence that links strep to PANDAS “inconclusive.”
Today Singer says that attempts in numerous studies to confirm the immune system as the “underlying mechanism in PANDAS have been equivocal.” As a result, he and other doctors say the diagnosis isn’t strong enough to justify giving kids powerful courses of antibiotics, let alone treatments like intravenous immunoglobulin, or plasmapheresis, a blood-filtering process typically used to treat severe autoimmune diseases like lupus. Treatments and medications for OCD and ADHD already exist, they say, and should be enough.
Swedo agrees that traditional treatments—cognitive behavior therapy, for example—are part of the solution. “But if you culture for strep and treat early, you can abort the entire disease process,” she says. “That’s one of the reasons this controversy has been so painful.”
Since Swedo’s 1998 paper, researchers have used MRI scans to show enlarged, inflamed basal ganglia in the brains of kids with PANDAS. They’ve swabbed slices of monkey brain with strep cultures taken from PANDAS patients, and observed immediate reactions in the equivalent of basal ganglia tissue. The immediate response to antibiotics and immune-suppressants underscored the connection between the compulsions and volatility of children with PANDAS and their strep infections.
Swedo and her colleagues realize that mental disorders caused directly by infection or autoimmune reaction are the exception rather than the rule. “Not everybody who gets strep ends up with this autoimmune response,” says Hornig. “The majority of people are walking around with anti-brain antibodies, but are perfectly healthy. How can that be?”
The answer is that, as appealing as the “one bacteria, one reaction, one cure” model of mental illness may be, most cases can’t be explained by looking at the immune system alone. Both advocates and critics of PANDAS agree that mental disorders like OCD, depression, or schizophrenia, in children and adults, should be looked at as a set of symptoms with a variety of possible causes. Genes, environment, and immunity all interact in ways doctors are just beginning to unravel.
As doctors and scientists return to an earlier, holistic understanding of the relationship between body and brain, they are potentially gaining new treatments for terrifying illnesses. Knowing that at least some mental disorders are caused by infection puts a new set of tools at doctors’ disposal. Swedo, who today is chief of the Pediatrics and Developmental Neuroscience Branch at NIMH, says this new thinking offers tremendous hope. “The most important fact is just because we don’t know what caused it doesn’t mean it’s not real, and it’s not in the brain,” she says.
Andrew Curry is a journalist in Berlin, Germany. He has written for a wide range of publications, including Archaeology, Discover, National Geographic, and Wired. You can follow him on Twitter @beonetony and also now about Google Earning
BY ANDREW CURRYILLUSTRATION BY HADLEY HOOPER
First described centuries ago, Sydenham’s chorea is a rare manifestation of rheumatic fever that affects children almost exclusively. It is a disconcerting, unmistakable illness to witness. Children are overcome by rapid, uncontrollable jerking of the hands, feet, and face, contorting their bodies in a distorted, disturbing “dance.”
Sydenham’s chorea is caused by molecular mimicry gone wrong. Molecular mimicry generally works like a wolf in sheep’s clothing. Streptococcus bacilli have thrived through the eons by cloaking themselves in proteins that resemble their host’s own cells. Disguised, it evades the immune system just long enough to establish an infection.
But sometimes this tactic sets off an unfortunate chain of events. When the immune system mounts its counterattack, it wipes out the wolf and the sheepskin it’s wearing. In classic rheumatic fever, the antibodies mistake the lining of the heart for strep bacilli. In Sydenham’s, the basal ganglia have a particularly fleece-y look. That, in turn, helps explain an afflicted child’s odd motions. The basal ganglia are walnut sized areas of the brain that serve as a sort of traffic light, signaling the muscles in the proper order to make voluntary movements.
When the basal ganglia are damaged or attacked, the disruption can be severe—as though the traffic light was permanently stuck on green. Everything from Parkinson’s and cerebral palsy to attention deficit hyperactivity disorder (ADHD) have been connected to damaged basal ganglia. “The basal ganglia are the gatekeeper between the brain stem and motor function and the upper brain. They say ‘stop, go, stop, go,’ ” says Swedo. “When they don’t work right, think of the gate as stuck open in certain areas—it’s a failure to inhibit the motor impulse in blinking or twitching.”
Just as puzzling are kids who don’t get PANDAS. That’s led to more than a decade of debate over whether it exists at all.
As Swedo collected case histories of children with OCD, Swedo began to notice remarkable parallels with Sydenhams.’ Most cases of OCD come on slowly, with tics accumulating and intensifying over months and years. But in about a quarter of the childhood-onset OCD cases Swedo looked at, the compulsive behavior came on like a light switch, going from normal to severe overnight. It was often accompanied by tics, like throat clearing and grunting; severe separation anxiety; bed-wetting; and changes in handwriting as fine motor control broke down.
Like rheumatic fever and Sydenham’s chorea, Swedo found, children whose OCD, tics, separation anxiety, and other symptoms came on suddenly often had strep infections not long before their first symptoms appeared. If strep could cause Sydenham’s, she wondered, could it also be affecting kids’ thoughts and behavior? In a 1998 paper, she proposed a link between strep, OCD, and the other symptoms she was seeing, calling the phenomenon “pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections,” or PANDAS.
Isak McCune’s experience is typical of PANDAS. In classic autoimmune diseases like Type 1 diabetes or lupus, the immune system spontaneously mistakes cells in the body for invaders. In PANDAS and Sydenham’s chorea, Swedo says, the attack is set off by an actual infection. As long as the immune system senses strep in the body, it produces antibodies tailored to fight the bacteria.
In people with PANDAS, though, the antibodies slip through the blood-brain barrier to attack similar-looking proteins on the cells of the basal ganglia. “The antibodies are somewhat sloppy; they cross-react with other proteins and chemicals,” says Hornig. “That can lead to changes in behavior or the brain.”
When it comes to treatment, the presence of strep antibodies in the blood of children with OCD is a positive sign. Remove the infection, and the crippling behaviors often go away, too. Once their bodies stand down from the fight against strep, the “cross-reactive” attacks on the basal ganglia seem to stop as well.
Artificially dampening the immune system seems to work in a similar way. Tricia Lord, a California parent whose son Kirk was treated for PANDAS in 2011 with steroids, an immunosuppressant, says she saw improvement within hours. “He was back to what he was before all this happened,” Lord says. “I couldn’t believe it. He seemed better than 100 percent.” (Kirk relapsed after a month, and doctors tried intravenous immunoglobulin, a procedure, designed to regulate the immune system, that infuses patients with antibodies extracted from healthy donors.1 He’s now off all medications and performing above his grade level.)
Much remains mysterious, Swedo says, about the symptoms of PANDAS. One of her early PANDAS cases was a 12-year-old girl convinced she caught rabies from an unopened hypodermic needle she found in her pediatrician’s parking lot. At the age of 5, Kirk Lord developed severe separation anxiety almost overnight, and sunk into a listless state his parents dubbed “the Fog.” Other kids afflicted with PANDAS hear voices or experience “Alice in Wonderland” syndrome, wildly distorted perceptions of size and distance some liken to waking nightmares. “Why is it rabies, or AIDS, or spearmint gum? Some are so random you scratch your head,” Swedo says.
Just as puzzling are the kids who don’t get PANDAS. Strep can be dangerous, but it’s a common part of childhood. The average grade school student comes down with strep twice a year, according to the National Institutes of Health. Yet 1,999 out of 2,000 don’t develop PANDAS. And Swedo estimates that PANDAS accounts for just 10 or 20 percent of all pediatric-onset OCD cases.
That’s led to more than a decade of debate over whether PANDAS exists at all. When Swedo and her colleagues first published their PANDAS results, there was a backlash from Harvey Singer, a professor of neurology and pediatrics at Johns Hopkins University, and Tourette’s researchers, who questioned the idea that a common childhood illness caused tics and OCD. In an influential 2011 Journal of Pediatrics paper, Singer called the evidence that links strep to PANDAS “inconclusive.”
Today Singer says that attempts in numerous studies to confirm the immune system as the “underlying mechanism in PANDAS have been equivocal.” As a result, he and other doctors say the diagnosis isn’t strong enough to justify giving kids powerful courses of antibiotics, let alone treatments like intravenous immunoglobulin, or plasmapheresis, a blood-filtering process typically used to treat severe autoimmune diseases like lupus. Treatments and medications for OCD and ADHD already exist, they say, and should be enough.
Swedo agrees that traditional treatments—cognitive behavior therapy, for example—are part of the solution. “But if you culture for strep and treat early, you can abort the entire disease process,” she says. “That’s one of the reasons this controversy has been so painful.”
Since Swedo’s 1998 paper, researchers have used MRI scans to show enlarged, inflamed basal ganglia in the brains of kids with PANDAS. They’ve swabbed slices of monkey brain with strep cultures taken from PANDAS patients, and observed immediate reactions in the equivalent of basal ganglia tissue. The immediate response to antibiotics and immune-suppressants underscored the connection between the compulsions and volatility of children with PANDAS and their strep infections.
Swedo and her colleagues realize that mental disorders caused directly by infection or autoimmune reaction are the exception rather than the rule. “Not everybody who gets strep ends up with this autoimmune response,” says Hornig. “The majority of people are walking around with anti-brain antibodies, but are perfectly healthy. How can that be?”
The answer is that, as appealing as the “one bacteria, one reaction, one cure” model of mental illness may be, most cases can’t be explained by looking at the immune system alone. Both advocates and critics of PANDAS agree that mental disorders like OCD, depression, or schizophrenia, in children and adults, should be looked at as a set of symptoms with a variety of possible causes. Genes, environment, and immunity all interact in ways doctors are just beginning to unravel.
I just replaced my public email address with an https://t.co/C3uDFPoRNA profile. You can now reach me here: https://t.co/AXI2rZUn1l— BeOneTony (@beonetony) February 25, 2018
As doctors and scientists return to an earlier, holistic understanding of the relationship between body and brain, they are potentially gaining new treatments for terrifying illnesses. Knowing that at least some mental disorders are caused by infection puts a new set of tools at doctors’ disposal. Swedo, who today is chief of the Pediatrics and Developmental Neuroscience Branch at NIMH, says this new thinking offers tremendous hope. “The most important fact is just because we don’t know what caused it doesn’t mean it’s not real, and it’s not in the brain,” she says.
Andrew Curry is a journalist in Berlin, Germany. He has written for a wide range of publications, including Archaeology, Discover, National Geographic, and Wired. You can follow him on Twitter @beonetony and also now about Google Earning
Source: nautil.us