These are my notes for a presentation given by Dr Trifilleti (aka "Dr T") at the 2013 New England PANS/PANDAS Parent's Conference, entitled "The Neurological Basis of PANDAS/PANS".
The really striking hallmark of PANDAS is the suddenness of the change in a child, their character can seem to change dramatically overnight. The most striking changes can include: odd and meaningless behaviors (OCD), irritability and emotional outbreaks (emotional lability), disturbances in memory and attention, regression or loss of skills such as reading and writing, melancholia, in some cases there is dementia and hallucinations. "Disturbance of the moral sense, manifested frequently in a strange perverseness" is also listed but I do not know what he means. Turns out this list came from a book about Chorea by Dr Osler from 1894. Dr T is making the point that PANDAS is described in that book, just not given a name.
For the purposes of understanding and helping each patient, patients can be grouped by clinical presentation and now more and more by genetic testing results as well. This can help identify which interventions may help which children.
What are the symptoms?
Original 1996 definition of PANDAS (often referred to as the "Swedo Criteria" after Dr Susan Swedo of the NIH who developed them):
1) Onset of symptoms between age 3 and 11
2) Acute onset
3) Of motor/vocal tics and/or OCD
4) Temporally correlated with a Group A Beta-Hemolytic Strep (GABHS) infection
5) Possible presence of choreiform signs
He then discusses several cases as examples. One child (age 6) is diagnosed with strep throat and put on antibiotics, several weeks later sudden onset of facial blinking and humming sounds, school phobia and avoidance, separation anxiety including need to sleep with parents at night, sleep problems, improves with ibuprofen (due to anti-inflammatory effects), sustained improvement with proper treatment. Another case concerns a 12yo child diagnosed with walking pneumonia, treated with antibiotics, over the course of weeks the child gradually develops a fear of vomiting or seeing other people vomit, appetite decrease to the point of anorexia, separation anxiety, need to sleep with parents at night, other sleep problems, improvement on ibuprofen, sustained improvement with appropriate treatment. Another child (age 2) presents with an asthma-like illness and over the course of weeks develops extreme motor restlessness (appears manic), increased sensory sensitivity, repetitive and ritualized behavior (OCD), a diagnosis of PDD-NOS is considered, rapid improvement with ibuprofen, sustained improvement with appropriate treatment.
When facing a new disease there is always the question of "lumpers vs splitters"...which means how narrowly should it be defined? Narrower definitions make research easier, but broader definitions help more people, so this is always a dynamic process. He says that evidence clearly shows that this (PANDAS) is a real thing. He points out that people who don't believe something is real don't study it, so they are not as knowledgeable about it. The question is then what are the limits of the disease? When is something *not* PANDAS? He says seizures do not seem to be associated with PANDAS. He says he is seeing many more patients with Ehlers-Danlos Syndrome than he would expect by chance so there may be an association there.
From PANDAS to PANS- limitations of the strict PANDAS model
There are advantages to narrowly defining a new entity, especially one that is not likely to be well received by the medical community, but this narrow definition has many limitations, which then limits the number of patients who can be helped. These problems include the age range, the disorder can set in earlier than age 3 and later than age 11. It can can also set in in adults so is not necessarily a pediatric disease, although there is suspicion with adults that the onset may actually be a relapse. He says that Micheal Jenike MD, one of the leading figures in OCD research in this country, has an interest in adult PANDAS cases so it looks like this subset will be studied more in the near future. Dr. T even mentions one case of an 80yo woman who had an OCD flare from a UTI. The pathogenic trigger is not always strep. The onset is not always acute. The common denominator among all of this is inflammation. The inflammation is so central that improvement with ibuprofen is almost diagnostic.
He points out that strep is a very complex thing, and that he (and most doctors) receive one lecture about it in medical school. So it is not generally well understood. He recommends the book Gram Positive Pathogens by Vince Fischetti. Strep is highly adapted to and sophisticated in dealing with our immune system. Carriers are people who are asymptomatic and who intermittently shed strep. This is part of why he uses blood testing but not throat cultures. Strep can be in many places in the body in addition to the throat, including anal strep, Peyer's patches in the gut, etc. There are also some kids (he says about 10-20%) whose immune systems don't respond...they have positive throat cultures but do not have elevated ASO or AntiDNAse titers. There can be strep in the appendix.
The basic idea behind the switch to PANS has been to take the emphasis off of the strep (or really the pathogenic trigger altogether), because this was a major limit in kids getting help. Also, the disease was not well understood enough to warrant such a focus. The focus is more on the sudden onset of the symptoms, but includes a broader list of symptoms, with less emphasis on tics and an increased emphasis on changes in eating. The list is now more focused on anxiety, separation anxiety, irritability, behavioral changes, emotional lability, and aggression. PANDAS/PANS is a pervasive disorder and many kids present with a list of diagnoses (he calls them "alphabet soup kids") such as ADHD, OCD, ODD, etc. He says the kid with 5 different diagnoses is a sign of likely PANDAS. Pervasive means that all areas of development can be affected, like it is in autism (which is also called a pervasive disorder), and partly why he thinks the two are connected.
Discussions based on databases of PANS test results
Dr T has now been able to collect data on a large enough group of patients to start seeing patterns and trends emerge. He says there appear to be several peaks in the age of onset, and that his experience suggests that each age peak represents a somewhat different presentation. The earliest peak, between say 1 and 2 years, presents indistinguishably from autism. There also seems to be what he calls a "pediatric mania" that has an onset around age 2 characterized by extreme hyperactivity. He says that over time this group has a likelihood of being diagnosed PDD-NOS. This group also tends to have a very atypical reaction to stimulant meds and SSRIs. In general this is so common among PANDAS kids that he thinks it should be in the diagnostic criteria- the atypical response to stimulant meds and SSRIs. The juvenile onset, which occurs on average around age 8, is the most common by far, and this group seems to fit the Swedo criteria the most. Another doctor has identified what seems to be a subgroup of kids whose onset is a little later, late junior high or high school, and who are characterized by OCD and anxiety without the tics present. This is often misdiagnosed as "conversion disorder". This is often a child who was a star student, athlete, socially popular, and then is suddenly stricken and disappears socially. Then there is what he calls "exorcist syndrome", which are flares in which the child develops a sudden rage response which can include a change in voice and carriage, flailing arms, etc, and then can shut off quickly (at least sometimes). The child often does not remember what happened. He says this is the "seizure" of PANDAS. He recommends that parents videotape these episodes to show to the doctor.
Mechanisms of PANS
There are two basic models of what causes this disorder, the first being one of molecular mimicry (strep triggers an autoimmune response that attacks part of the brain due to molecular mimicry), and an altered fever response. The first explanation is about pathogens acting as triggers and being the agents of the disorder, the second is about a problem in our own bodies that does not emphasize the pathogens involved. PANDAS is an interaction between your immune system and your brain, it is a neuroimmune disease. These are the two most complex parts of our bodies, so trying to understand PANDAS is trying to understand the interaction between the two most complicated and sophisticated networks in our body. He described them both as "fractally complicated" which I think is a wonderful way to describe it.
Our immune systems can be roughly divided into two parts- innate immunity and acquired immunity. We are born with the innate system, which occurs on a cellular level and includes cytokines, the complement system, basically everything except antibodies which is the acquired system. The acquired immune system involves T-cells that have memory, they've seen things before and can learn from past experiences. Vaccines are meant to work with the acquired (also called adaptive) immune system. He says that when people are young, the innate immune system seems to be particularly important, and as we age, the adaptive system takes over in importance. The innate immune system to some extent controls the adaptive system. Cytokines are the signals that immune cells use to communicate with each other in order to coordinate their responses. He says the mother essentially gives the fetus an infusion of immunoglobulins during gestation (could this be some of the familial connection? Maybe PANDAS kids are born to mothers whose immune dysregulation didn't allow that process to happen correctly?).
Molecular mimicry is well established to exist as an immune problem, especially outside the brain. The explanation does fit for much of the PANDAS picture. However there are some problems with this theory as the basis of PANDAS. With so many pathogenic triggers, including different bacteria, even viruses and parasites, how can they all lead to molecular mimicry of the same brain region? PANDAS triggers can even be non-infectious processes. The different pathogenic triggers lead to indistinguishable phenotypes. How do such large molecules as antibodies get across the blood-brain-barrier? There are ways in which that can happen. Why is the onset usually so sudden- can antibodies really get into the brain that quickly? With the exception of anaphylaxis, antibody-mediated disease just doesn't happen that quickly.
This disease evolves over time, the mechanisms change over time, especially if the person goes untreated. Many of the children either do not get fevers or will suddenly do very well when they have a fever. Looking at the data he has gathered, there is clearly a low ASO-titer group. 52% of kids had high ASO-titers according to LabCorp criteria, mycoplasma is positive in about 75% (IgG), and about 12% are positive for IgM (which is more meaningful), Coxsackie B is positive in about a third of patients (type B5 being the most important one), and about 6% are positive for Lyme (which is probably an underestimation). He shows a list of infections that are associated with PANDAS at 50:20. In about 13% of kids no pathogenic trigger is ever found. The combination of Coxsackie B and strep can be particularly bad due to an antigenic complementarity.
Looking on the host side, there are abnormalities in the humoral immune system in people with PANS. About 25% of kids have one or more abnormal Ig levels, excluding IgE which has a lot of variability. About 10% have low IgG. There are also deficiencies seen in subclasses of Igs, in particular IgG. This is discussed around 54:00. There is a group that is about 1 in 30 people with PANDAS, all boys, who have an elevated IgA and low IgM, such that the ration of IgA to IgM is greater than 10, which is seen in an immunodeficiency disease called Wiskott-Aldrich Syndrome. About 5% meet criteria for Common Variable Immunodeficiency (these kids NEED IVIG). Basophil levels are always low (unless there is a parasitic infection). There can also be IgE abnormalities, there is a low IgE subgroup, and a rarer high IgE group. The low IgE and low IgG4 groups seem to go together and be a subtype. What makes IgE and IgG4 go low? It's the IL4 a IL13 cytokines, which have also been found to be low in some people with PANS. IL10 is also often dysregulated in PANS. PANS puts the immune system in an anti-allergic or anti-anaphylactic state. He has a theory that PANDAS exists as an evolutionarily driven protection against anaphylaxis. He also says that PANDAS people have low histamine levels. He postulates that PANDAS is a fever response taking a wrong turn. The locus of action is in the hypothalamus. When a normal immune phenotype encounters a trigger, you get a fever. When a PANS-phenotype encounters a trigger, you get PANS. He thinks it's all a matter of the host.
In gene studies around 36% of kids with PANDAS have abnormal microarrays (which look for deletions of genes), which is a very high amount. About 60% of those people have PDD type PANS. The corresponding rate in autism is around 10-20%. 10% of the positive microarrays that they did had an association with the Prader-Willi region which is interesting because Prader-Willi Syndrome is a well known biological cause of OCD. There is also a correlation with some of the mito genes, in particular the ones associated with a class of proteins called peroxiredoxins, which have a role in regulating free radical generation. If this correlation proves to be meaningful it may suggest a treatment option (namely to address the excess free radicals being generated). He suggests that there is a connection with Nitric Oxide production but doesn't elaborate. This could be interesting because nitric oxide is deficient in people with MTHFR.
Summary
PANS is a common disorder with a wide range in manifestations, including tics, OCD and other symptoms, he thinks there are at least 4 clinical sub-syndromes, there is a remarkable response to prostaglandin inhibitors and ibuprofen in many patients, has many different triggers, the mechanism is largely an alternative fever response, molecular mimicry in at least some cases, and as time goes on the autoantibodies become more and more important. Dysregulation of the immune system, immunodeficiency, and eventually autoimmunity are very common. Peripheral and central histaminergic mechanisms are important in pathogenesis. A number of genes are implicated as well.
Additional information from his slides, that was omitted from this lecture due to lack of time, can be found in this post.
