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PANDAS/PANS: A Constellation of Symptoms Searches for a Cause
In the 1990s, investigators at the National Institute of Mental Health (NIMH), including pediatrician Susan Swedo, MD, were conducting studies on OCD in childhood and observed that some children had a very sudden onset of symptoms rather than the typical gradual increase in OCD behavior. The appearance of the symptoms was abrupt and intense enough (reaching full throttle in 24–48 hours) that parents often could pinpoint the day their child went from being normal and happy to engaging in repetitive behaviors (or not eating) and exhibiting tics. The accompanying neuropsychiatric symptoms often included frequent tantrums, severe separation anxiety, an inability to learn in school, regressive behaviors including baby talk, and urinary incontinence. “I lost my child overnight” was, and is, a common refrain.
Dr. Swedo (who today is the chief of the Pediatrics & Developmental Neuroscience Branch at NIMH) and her fellow researchers soon discovered that this constellation of symptoms tended to occur after a viral or bacterial infection such as influenza, chicken pox, or strep throat. The scientists decided to focus on OCD that occurred in the wake of streptococcal infections (which are caused by Group A streptococcus, or GAS) because of the long-known connection between OCD symptoms and a post-streptococcal neurologic disorder, Sydenham’s chorea (also known as St. Vitus’ dance). Sydenham’s chorea is characterized by rapid and irregular involuntary movements typically with OCD and other emotional symptoms, all of which usually emerge 6–12 months after infection.
Dr. Swedo and her colleagues called the sudden-onset, post-streptococcus infection syndrome Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections, or PANDAS.
The search for a mechanism
Strep bacteria are thought to cause neurologic damage in a Trojan horse kind of way. The National Institute of Mental Health posits that they hide in their human host for as long as possible by putting molecules on their cell walls that look identical to molecules found on a child’s brain tissue (as well as heart and joint tissue). When the immune system finally recognizes the bacteria for the invaders they are, its antibodies attack; however, in the process, they also attack the brain tissue that has been “mimicked”—tissue in the basal ganglia specifically, it is believed. That’s apparently what causes the chorea. Various researchers think some of the antibodies of the immune system don’t cause Sydenham’s chorea but instead cause the signs and symptoms of PANDAS.
Strep isn’t associated with all cases of abrupt-onset OCD, however. Indeed, an accompanying infection, strep or otherwise, cannot always be found. That’s in part why the term PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) was coined in 2010, a dozen or so years after the PANDAS acronym. PANS is an umbrella term that includes all cases of OCD that appear out of nowhere (with accompanying ancillary symptoms) and whose etiology might not be associated with infections (streptococcal or otherwise) but perhaps with metabolic, inflammatory, or other factors. Diagnostic criteria for PANS and PANDAS, which have a fair amount of overlap but differ in certain details, can be found in the table on page 5.
Both PANS and PANDAS are more likely to affect boys over girls by a ratio of 2 to 1, and the usual age of onset is 7 to 9. The typical history is that a hitherto normal child suddenly develops severe problems. These may include refusing to leave the house, engaging in constant checking and washing rituals, asking repeatedly if the door is locked, making odd facial movements, having full-on tantrums with kicking and screaming, wetting the bed, and being unable to perform in school. The symptoms follow an on-again-off-again course with relapsing and remitting symptoms, suddenly flaring and gradually resolving with time and/or treatment.
Although most authorities agree that the PANDAS/PANS symptoms pattern exists, the etiology is in dispute, and it is not yet listed as a diagnosis in either ICD or DSM. One complicating factor is the almost ubiquitous nature of strep bacteria, with or without illness—it can be found in the throat cultures of many kids who are not sick. In other words, it’s easy to erroneously associate psychiatric symptoms in a child with strep because strep is often present.
Potentially confounding the diagnosis is that OCD and tics often flare and subside as part of their natural course. Parents may report an apparent “sudden onset” of symptoms—leading to a workup for PANDAS—when in fact the behaviors have been present for some time, but at a milder level.
Much laboratory research has been done, but the results have been mixed, with some studies reporting a link between streptococcal infections and the acute presentation of PANDAS symptoms, but others not (Murphy TK et al, J Clin Child Adolesc Psychol 2010;20(4):317–331). On the one hand, researchers have had some tantalizing results tying strep to PANDAS with animal models. In one experiment, investigators exposed rats to the strep antigen and then observed changes that included compulsive behavior and various motor symptoms. They found, too, that exposure to strep resulted in deposits of antibodies in various parts of the brain and alterations of dopamine and glutamate levels consistent with those of Sydenham’s chorea. They even found alleviation of symptoms with haloperidol and paroxetine (Brimberg L et al, Neuropsychopharmacology 2012;37(9):2076–2087).
But other researchers, comparing antibody levels in the basal ganglia of children with PANDAS to the antibody levels in the basal ganglia of children without the disease, found no difference (Singer HS et al, Movement Disorders 2004;19(4):406–415). It seems like a smoking gun—ready, aim, with a reasonable line of research delineated—but a proven mechanism remains elusive.
Still, kids are coming in with these symptoms. The syndrome, whatever is causing it, is real, and children who are sick have to be treated—and they are, at some of the top institutions in the country. But how exactly should treatment proceed? In the accompanying interview, Dr. Erica Greenberg at Massachusetts General Hospital covers diagnosis and treatment of this perplexing, and interesting, condition.
Child PsychiatryDr. Swedo (who today is the chief of the Pediatrics & Developmental Neuroscience Branch at NIMH) and her fellow researchers soon discovered that this constellation of symptoms tended to occur after a viral or bacterial infection such as influenza, chicken pox, or strep throat. The scientists decided to focus on OCD that occurred in the wake of streptococcal infections (which are caused by Group A streptococcus, or GAS) because of the long-known connection between OCD symptoms and a post-streptococcal neurologic disorder, Sydenham’s chorea (also known as St. Vitus’ dance). Sydenham’s chorea is characterized by rapid and irregular involuntary movements typically with OCD and other emotional symptoms, all of which usually emerge 6–12 months after infection.
Dr. Swedo and her colleagues called the sudden-onset, post-streptococcus infection syndrome Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections, or PANDAS.
The search for a mechanism
Strep bacteria are thought to cause neurologic damage in a Trojan horse kind of way. The National Institute of Mental Health posits that they hide in their human host for as long as possible by putting molecules on their cell walls that look identical to molecules found on a child’s brain tissue (as well as heart and joint tissue). When the immune system finally recognizes the bacteria for the invaders they are, its antibodies attack; however, in the process, they also attack the brain tissue that has been “mimicked”—tissue in the basal ganglia specifically, it is believed. That’s apparently what causes the chorea. Various researchers think some of the antibodies of the immune system don’t cause Sydenham’s chorea but instead cause the signs and symptoms of PANDAS.
Strep isn’t associated with all cases of abrupt-onset OCD, however. Indeed, an accompanying infection, strep or otherwise, cannot always be found. That’s in part why the term PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) was coined in 2010, a dozen or so years after the PANDAS acronym. PANS is an umbrella term that includes all cases of OCD that appear out of nowhere (with accompanying ancillary symptoms) and whose etiology might not be associated with infections (streptococcal or otherwise) but perhaps with metabolic, inflammatory, or other factors. Diagnostic criteria for PANS and PANDAS, which have a fair amount of overlap but differ in certain details, can be found in the table on page 5.
Both PANS and PANDAS are more likely to affect boys over girls by a ratio of 2 to 1, and the usual age of onset is 7 to 9. The typical history is that a hitherto normal child suddenly develops severe problems. These may include refusing to leave the house, engaging in constant checking and washing rituals, asking repeatedly if the door is locked, making odd facial movements, having full-on tantrums with kicking and screaming, wetting the bed, and being unable to perform in school. The symptoms follow an on-again-off-again course with relapsing and remitting symptoms, suddenly flaring and gradually resolving with time and/or treatment.
Although most authorities agree that the PANDAS/PANS symptoms pattern exists, the etiology is in dispute, and it is not yet listed as a diagnosis in either ICD or DSM. One complicating factor is the almost ubiquitous nature of strep bacteria, with or without illness—it can be found in the throat cultures of many kids who are not sick. In other words, it’s easy to erroneously associate psychiatric symptoms in a child with strep because strep is often present.
Potentially confounding the diagnosis is that OCD and tics often flare and subside as part of their natural course. Parents may report an apparent “sudden onset” of symptoms—leading to a workup for PANDAS—when in fact the behaviors have been present for some time, but at a milder level.
Much laboratory research has been done, but the results have been mixed, with some studies reporting a link between streptococcal infections and the acute presentation of PANDAS symptoms, but others not (Murphy TK et al, J Clin Child Adolesc Psychol 2010;20(4):317–331). On the one hand, researchers have had some tantalizing results tying strep to PANDAS with animal models. In one experiment, investigators exposed rats to the strep antigen and then observed changes that included compulsive behavior and various motor symptoms. They found, too, that exposure to strep resulted in deposits of antibodies in various parts of the brain and alterations of dopamine and glutamate levels consistent with those of Sydenham’s chorea. They even found alleviation of symptoms with haloperidol and paroxetine (Brimberg L et al, Neuropsychopharmacology 2012;37(9):2076–2087).
But other researchers, comparing antibody levels in the basal ganglia of children with PANDAS to the antibody levels in the basal ganglia of children without the disease, found no difference (Singer HS et al, Movement Disorders 2004;19(4):406–415). It seems like a smoking gun—ready, aim, with a reasonable line of research delineated—but a proven mechanism remains elusive.
Still, kids are coming in with these symptoms. The syndrome, whatever is causing it, is real, and children who are sick have to be treated—and they are, at some of the top institutions in the country. But how exactly should treatment proceed? In the accompanying interview, Dr. Erica Greenberg at Massachusetts General Hospital covers diagnosis and treatment of this perplexing, and interesting, condition.
PANDAS: When Medicine Doesn’t Help
In severe, refractory cases of PANDAS in which antibiotics, steroids, NSAIDs, and other medicines have not mitigated symptoms, some clinicians have been turning to plasmapheresis (plasma exchange) and intravenous immunoglobulin therapy (IVIG). In theory, plasma exchange works by removing all antibodies and replacing them with antibodies from healthy donors. Meanwhile, IVIG theoretically deliveries antibodies from healthy donors that dilute the “bad” antibodies of a child with PANDAS. But it is not known how either treatment actually works.
It’s also not known with certainty whether they work. Some case studies indicate they do, and a placebo-controlled double-blind study conducted before 2000 suggested that both IVIG and plasma exchange reduced OCD symptoms in children with PANDAS, by 45% and 58% respectively (Perlmutter SJ et al, Lancet 1999;354(9185):1153–1158).
But Dr. Greenberg’s colleague, Kyle Williams, MD, PhD, of the Pediatric Neuropsychiatry and Immunology Program at Massachusetts General Hospital, found more recently that IVIG failed to demonstrate any benefit over placebo (Williams KA et al, JAACAP 2016;55(10):860–867.e2).
Given the uncertainties about the role of these treatment approaches, anyone considering plasma exchange or IVIG should make the decision in consultation with an immunologist or infectious disease expert.
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