What Is PANDAS/PANS?

No Fluffy Bear Here.

PANDAS= Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections

PANS= Pediatric Acute-Onset Neuropsychiatric Syndrome.

So what is PANDAS anyway? The cute fluffy bear that lives in Asia? Well, no. This PANDAS actually stands for Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS). In 1998, criteria for PANDAS was established after several children were presenting with a particular combination of symptoms, including, OCD, tics, separation anxiety, inattention, and sometimes neurological abnormalities such as or “brain fog”, after a group-A beta-hemolytic strep infection somewhere between age 3 and puberty. These symptom were observed to have an abrupt onset and variable/episodic course, including “flare ups.”

In 2012, there were a subset of children, who had similar symptoms to PANDAS; however, they had not tested positive for strep. These children were experiencing OCD-type behaviors, inattention, tics, restricted food intake, incontinence, anxiety/irritability, sensorimotor differences, REM sleep dysfunction, and developmental or academic regression. And so, a new label came into play: Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS).

Of note, most children diagnosed with PANDAS in the US are white, live in more urban areas, and there are typically even distributions across males and females. Per the research, the most frequently reported symptom was OCD behaviors; not tics, jerking movements, incontinence, or other neurological complaints, and the strongest potential indicator for PANS and PANDAS is the “acute” onset and “flare ups.”

On neuropsychological assessment, many PANDAS children had reduced visuospatial memory, reduced inhibitory control, reduced fine motor speed, and reduced sustained attention. Children diagnosed with PANS typically had more exacerbated deficits, especially within processing speed and memory measures and tended to experience incontinence more so than children diagnosed with PANDAS. Across both PANS and PANDAS the profile of strengths and weaknesses were consistent with symptoms reported, and there were minimal differences in behavioral or emotional concerns as compared to children with OCD, ADHD, tic disorder and/or anxiety who presented for testing.

Neuroimaging studies have shown inflammation in the caudate nucleus, putamen, globus pallidus, and lentiform nuclei, all parts of what is called the basal ganglia, though research on specific areas affected has been variable. The basal ganglia is a part of the brain responsible for motor learning, motor control, habit formation, and execution of behavior and emotions.

So what is the theory posited to explain how PANS and PANDAS develop in the human body? Common illnesses such as: pharyngitis (fancy word for sore throat), rhino sinusitis (sinus infection), acute ear infections, obstructive sleep apnea, and tonsillitis, which are most often caused by a primary viral infection or bacterial strep, can lead to secondary infection. It has been shown that chronic adenoid/tonsil tissue inflammation can play an important role in many system illnesses including autoimmune diseases.

The leading theory is that when the body experiences either a strep or other viral infection (COVID, Epstein-Barr, Lyme Disease etc.), anti-neuronal antibodies are formed and act as a trigger against the the body and brain and affect the function and neurotransmission of certain dopamine (a type of neurotransmitter) receptors within the basal ganglia. The antibodies also may bind to acetylcholine and GABA (two more neurotransmitters) interneurons in the brain, which can result in compulsive behaviors, when these cortical circuits are disrupted. These antibodies may cross-react with brain proteins, mostly within the basal ganglia, and cause inflammation. Impairment in dopaminergic circuits in the basal ganglia provokes neurological symptoms, similar to what is seen in Tourette’s and other disorders with repetitive behaviors. The 3-4 types of dopamine receptors that are suspected to be disrupted are together considered the “Cunningham Panel,” which is a test intended to measure immune dysfunction secondary to infection, so when a child has a positive Cunningham Panel, that is said to be potential evidence for PANS or PANDAS.

In terms of research pertaining to PANS/PANDAS treatment, because immunotherapy has helped with other bacterial and viral infections as well as in some cases of long-COVID, some hypothesized it may be beneficial. In terms of the research, immunotherapy (corticosteroids, NSAIDS, IVIG, plasma exchange) has demonstrated variable efficacy in terms of creating an immunomodulatory effect. There were some studies showing improvement from IVIG; however, most did not have blinding, placebo, or control groups, and more robust studies failed to show any improvement from intravenous immunoglobulin (IVIG). Additionally, there were occasionally some unnecessary adverse effects to antibiotic treatment, especially IVIG. Moreover, there was no benefit from penicillin prophylaxis in terms of tics or OCD symptoms when randomized double-blind study. In one study, Azithromycin demonstrated minor reduction in OCD symptoms but not reductions in other neuropsychiatric symptoms. As compared to Azithromycin, SSRI + CBT and CBT alone were both superior in treatment outcomes. Long-term use of penicillin prophylaxis did not reduce OCD and tic symptomatology but did reduce the prevalence of strep infections. For Intravenous Immunoglobin (IVIG) several studies reported improvement but limited randomized-controlled trials. IVIG reportedly resulted in reduction of symptoms for both those diagnosed with PANDAS and healthy controls. There was also variable benefit from tonsillectomy/adenoidectomy, but only via individual case studies. When patients received CBT and SSRIs (Zoloft, prozac etc.) this was found to be beneficial for PANDAS, similar to individual diagnoses themselves. And finally, per a recent systemic review on PANS and PANDAS, there has been “Conclusive evidence is largely lacking regarding potential beneficial effects of anti-inflammatory, antibiotic, and immunomodulatory treatments for children with symptoms corresponding to PANS/PANDAS; however, this may meant a mismatch between diagnosis and treatment for individual cases so its not a black and white issue.

While there may be some initial inflammation during and shortly after a virus, there has been inconsistent evidence of ongoing inflammation for PANS/PANDAS children, despite ongoing symptoms. There are also many potential confounding factors (illness, age, genetics, medication) that may make it challenging to understand when or how symptoms present. Those with strep seem to be more vulnerable to mental disorders overall, perhaps due to similar genetic make-up/loading on similar chromosomes. Because of this convoluted diagnostic process and significantly variable course and presentation, it has been challenging for clinicians to accurately diagnose with one or two specific tests. Many studies demonstrated no observed differences in symptoms between those who were positive or negative when tested via the Cunningham panel, indicating a lack of correlation between increased dopamine receptors/inflammation and PANS/PANDAS symptoms. The role of antibiotics in preventing exacerbation of OCD and tic symptomatology has not been consistently established. Additionally, several studies failed to identify significant differences in specific serum antibodies between PANDAS and control patients. Importantly, there were no clear differentiation in OCD or tic disorders for those with and without PANDAS and no notable biomarkers or distinct clinical characteristics.

So then, if we know a possible way of infections affecting the brain, then why the controversy? Well, in short, since the term PANDAS first gained popularity in the early to mid 2000s, there has been a lack of agreement about criteria, course, and etiology for PANDAS. Additionally, there has been inconsistent application of PANS and PANDAS diagnostic criteria, potentially resulting in an overly broad application of the diagnosis (other cause aside from immune response), as they are both ultimately diagnoses of exclusion, especially as strep titers can give a false positives and there are many different ways neuro-anatomically and neuro-chemically to produce OCD and Tourettes symptoms, with no unique neurobiological profile. Moreover, there is significant variability in the “acuteness” of onset, resulting in some not meeting criteria for that reason. This is further complicated as a result of the nexus of infection, immunology, and mental health differences with lack of uniformity and thus variable medical and psychiatric treatment. As such, there are currently no established or agreed upon recommendations or standardized protocols for treatment of PANDAS and many doctors prefer different antibiotic regimens or alternate therapies. As such, this has resulted in confusion for many pediatricians in terms of difficulty knowing when and how to refer, as well as fear of potential unnecessary treatments/cost, and resistance to antibiotics when give unnecessarily. Additionally, Gilbert et al. (2018) stated “There remains a pressing need to better define clinical manifestations, laboratory and neuroimaging findings, therapeutic responses, and clinical course to prevent overuse of antibiotics and unwarranted exposure to powerful immunomodulatory agents” and Sigra et al. (2018) explained the problem with identifying effective treatments is that “Rigorously conducted research regarding treatment is scarce and appears to have a high risk of bias.”

So what are the recommendations if you feel your child may meet criteria for PANS or PANDAS after a recent infection or recent onset of behavioral symptoms? There are many clinical decision trees to assist doctors with this questions but of course the first step is to bring your children to an expert or someone capable of referring you to an expert. If a child presents with acute onset tics/OCD/food restriction, they may need a full medical workup, throat swab, blood work with blood cell count and manual differential, inflammatory markers, metabolic panel, and urinalysis. And if they have chorea/jerking movements, they may benefit from an infectious disease or neurological evaluation. Sometimes a lumbar puncture with cerebrospinal fluid evaluation to look for antineuronal antibodies would be recommended if significant neurological symptoms and/or EEG abnormalities; however, this would only be warranted in severe cases. If physical exam is normal, doctors may consider antibiotics/immunotherapy in severe cases and/or corticosteroids or NSAIDS, which may be helpful during “flare ups”, to reduce inflammation (with doctor’s advice and prescription). They may also refer to psychiatry, and/or typical psychotherapeutic and psychiatric treatment.

All in all, this is a complex diagnosis, with many potential professionals involved, so it is important to advocate for yourself or your child and attempt to find consistent opinions across doctors and do your best to avoid any unnecessary testing or treatments. Often times it is very appealing to find “an answer” or “a label”; however, we know this can also sometimes create more confusion and reinforce a “sick label” for a child who potentially is not substantially ill. Your best bet is to treat the symptoms in front of you: if your child has a viral or bacterial infection, treat the viral infection according to the corresponding medical protocol recommended by your medical doctor, which can sometimes involve antivirals, antibiotics, or plasma exchange. If your child has repetitive behaviors/compulsions or anxiety, it may be recommended that you treat those symptoms with the aid of a psychiatrist or psychologist through CBT or appropriate psychotropic medication (SSRIs, clonidine, or neuroleptics).