From Paresis to PANDAS & PANS

In a visit to a mental asylum in 1912 you would have seen many patients with “general paresis.” The word “paresis” is Latin for weakness. General paresis was a form of psychosis with delusions, hallucinations, and memory problems often of rapid onset and thought to be due to a general constitutional weakness. At least that was the explanation until 1913, when general paresis was shown to be caused by syphilitic infection of the brain. The first treatments were awarded a Nobel Prize in 1917. The advent of antibiotics 30 years later led to the virtual eradication of neuro-syphilis, as the disorder came to be called, in this country.

The idea that mental or behavioral disorders could be due to infection is, therefore, not new but it remains surprisingly difficult to accept. When I was in training in the 1970’s, peptic ulcer disease was the prototype of a “biopsychosocial” disorder, with stress and a Type A personality considered the causes and psychodynamic therapy recommended as the treatment. Although helicobacter pylori was identified as the cause of peptic ulcer disease by Australians Robin Warren and Barry Marshall in the 1980’s, there was very little awareness (within the mental health community) that the disorder could be cured with antibiotics until Warren and Marshall received the Nobel Prize in 2005.

We may be looking at a similar reluctance to accept an infectious cause of pediatric sudden onset obsessive compulsive disorder (OCD) – in a debate that has been ongoing for almost two decades. In the early l990s, pediatrician Dr. Susan Swedo identified a subgroup of children whose OCD symptom onset didn’t fit the typical pattern. Instead of emerging gradually over weeks or months, they experienced ferocious bouts of compulsive behaviors and other symptoms “overnight and out of the blue.” As a pediatrician, Swedo’s familiarity with the ways of infectious agents and autoimmune mechanisms, together with her careful observations in the child psychiatry clinic of the NIMH Intramural Research Program, sparked the surprising hypothesis that a strep infection could trigger OCD symptoms via an autoimmune process.

This proved more complicated than syphilis or helicobacter. Part of the problem has been that strep is very common in childhood, making it methodologically difficult to prove a causal connection between the microbe and the OCD symptoms. The onset has not always been linked precisely with a strep infection and the critical increase in antibodies to strep has not been evident consistently. Nevertheless, immune-based treatments have proven successful, leading to the growing acceptance of the concept of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS).

Fortunately, the field is moving toward consensus on some of the larger issues, such as a broader concept of “acute and dramatic” onset of the same profile of psychiatric symptoms identified in PANDAS – but of unknown cause. There is also consensus on the need to establish a centralized registry to facilitate data analysis, so that causes and appropriate treatments can eventually be pinpointed.

This rapprochement recently took form in criteria for a broadened syndrome of acute onset OCD, published last month by Swedo, James Leckman at Yale and Joel Rose at Johns Hopkins. Their proposed Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) builds on and subsumes PANDAS. It embraces youth who experience acute onset of OCD or anorexia symptoms, mixed with a varying profile of other neuropsychiatric symptoms – cause unspecified.

Meanwhile, to strengthen evidence in support of immune-based treatment for the subset of youth whose illness is strep-related, Swedo, Leckman, and Madeleine Cunningham of the University of Oklahoma, and colleagues, are collaborating on a multi-site, double blind,placebo-controlled trial. It is testing intravenous immunoglobulin (IVIG) for OCD symptoms in PANDAS. IVIG, an infusion of normal antibodies, restores normal immune function by neutralizing errant antibodies. A similar pilot study testing IVIG and another immune-based treatment more than a decade ago found that all treated children with PANDAS improved, with more than half completely cured or experiencing only subclinical symptoms after one year.

Despite doubt in some quarters, hints of possible involvement of infectious agents and/or autoimmune processes in other serious brain disorders, such as autism, have spurred interest in PANDAS as a model for a type of illness process that may be more informative than widely assumed.

MRI scans of a PANDAS patient, showing reduced inflammation in the caudate nucleus(area circled just to the left of black area in center of brain), part of the basal ganglia, following IVIG treatment. Evidence suggests that this brain structure is targeted by errant anti-brain antibodies, triggered by a strep infection, in PANDAS.