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Details</a></p></div></div><div class="body-content whole_rhythm" itemprop="text"><div id="pandas.Introduction"><h2 id="_pandas_Introduction_">Introduction</h2><p>Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS) is proposed to be a nonsuppurative sequela of <i>Streptococcus pyogenes</i> or group A streptococcal infections. The disorder is characterized by the unusually fulminant onset of multiple tics or obsessive-compulsive disorder (OCD) in prepubertal children with a recent history of <i>S. pyogenes</i> infection (<a class="bibr" href="#pandas.REF.swedo.1998.264" rid="pandas.REF.swedo.1998.264">Swedo, et al., 1998</a>; <a class="bibr" href="#pandas.REF.swedo.2004.907" rid="pandas.REF.swedo.2004.907">Swedo, Leonard, & Rapoport, 2004</a>). Apart from the primary symptoms of OCD and/or tics, PANDAS is marked by the sudden onset of various psychiatric, behavioral, cognitive, and physical symptoms, including but not limited to anxiety (especially separation anxiety) and panic, emotional instability, developmental regression, irritability, heightened aggression, difficulties with concentration and attention, deficits in visuospatial skills, and other cognitive functions, as well as somatic symptoms like sensory sensitivities, sleep problems, and urinary issues like frequency, urgency, and secondary enuresis. The appearance of these symptoms concurrently and “out of the blue” allows clinicians to easily distinguish acute-onset presentations (now known as Pediatric Acute-onset Neuropsychiatric Syndrome or PANS) (<a class="bibr" href="#pandas.REF.chang.2015.3" rid="pandas.REF.chang.2015.3">Chang, et al., 2015</a>; <a class="bibr" href="#pandas.REF.swedo.2012.113" rid="pandas.REF.swedo.2012.113">Swedo, Leckman, & Rose, 2012</a>) from other, more typical cases of childhood-onset OCD or tic disorders. The diagnosis of PANS is based on a constellation of signs and symptoms that commonly occur together but does not provide insight into the underlying cause or mechanism of the condition. In contrast, a diagnosis of PANDAS requires not only an acute onset of neuropsychiatric symptoms, but also the temporal association of symptom onset due to a prior <i>S. pyogenes</i> infection or exposure to a person infected with <i>S. pyogenes</i>. Determining the link between <i>S. pyogenes</i> infection and symptom onset/exacerbation can be problematic for clinicians—overdiagnosis may occur because <i>S. pyogenes</i> infections are ubiquitous among grade-school aged children (<a class="bibr" href="#pandas.REF.kaplan.1980.337" rid="pandas.REF.kaplan.1980.337">Kaplan, 1980</a>; <a class="bibr" href="#pandas.REF.shaikh.2010.e557" rid="pandas.REF.shaikh.2010.e557">Shaikh, Leonard, & Martin, 2010</a>), which raises that possibility that “true-true-but unrelated” associations may be found; conversely, causative associations might be missed if the neuropsychiatric symptoms were triggered by an asymptomatic infection or (immunologically active) exposure to an undetected <i>S. pyogenes</i> carrier. The diagnostic process is further complicated by clinical and immunological overlap with other disorders, such as Sydenham chorea (<a class="bibr" href="#pandas.REF.kerbeshian.1990.642" rid="pandas.REF.kerbeshian.1990.642">Kerbeshian, Burd, & Pettit, 1990</a>; <a class="bibr" href="#pandas.REF.kiessling.1993.39" rid="pandas.REF.kiessling.1993.39">Kiessling, Marcotte, & Culpepper, 1993</a>). These clinical issues are partly responsible for the “controversy” surrounding PANDAS, a controversy which has negatively impacted the diagnosis and treatment of PANDAS for more than three decades. Fortunately, an emerging literature is helping to clarify the clinical profile of PANS and PANDAS and to provide guidance on the evaluative components needed to establish the diagnosis. There is also a growing body of evidence for the utility of a three-pronged approach to treatment that aims to control the <u>Symptoms</u>, stabilize the immune <u>System</u>, and eliminate the <u>Source </u>of antigenic stimulation (typically, a microbial infection) (<a class="bibr" href="#pandas.REF.swedo.2017.562" rid="pandas.REF.swedo.2017.562">Swedo, Frankovich, & Murphy, 2017</a>). Apart from a review of the clinical and epidemiological literature, this chapter will provide a summary of basic and translational research findings that shed light on the relationship between PANDAS and Sydenham chorea (SC), as well as the involvement of post-streptococcal neuroinflammation and immunological biomarkers in PANDAS and SC.</p></div><div id="pandas.PANDAS_as_a_Subgroup_of_OCD_and_T"><h2 id="_pandas_PANDAS_as_a_Subgroup_of_OCD_and_T_">PANDAS as a Subgroup of OCD and Tic Disorders</h2><p>Before discussing the unique clinical aspects of PANDAS, it is important to understand its place within the universe of OCD and tic disorder cases and its relationship to Sydenham chorea (SC), the neurologic manifestation of acute rheumatic fever.</p><p>Obsessive-compulsive disorder (OCD) is characterized by the presence of obsessions (recurrent, intrusive and unwanted thoughts, urges, or images) and/or compulsions (repetitive behaviors or mental acts that an individual feels driven to perform in response to an obsessional fear or according to rules that must be rigidly applied). In order to meet OCD diagnostic criteria, the symptoms must take up more than an hour per day (in aggregate) and cause clinically significant distress and/or functional impairments (<a class="bibr" href="#pandas.REF.schuyler.2023.89" rid="pandas.REF.schuyler.2023.89">Schuyler & Geller, 2023</a>). Epidemiologic studies of OCD in children and adolescents have reported prevalence rates ranging from 0.25% to 3%, with most studies reporting frequencies of approximately 1% (<a class="bibr" href="#pandas.REF.giedd.2000.281" rid="pandas.REF.giedd.2000.281">Giedd, Rapoport, Garvey, Perlmutter, & Swedo, 2000</a>; <a class="bibr" href="#pandas.REF.heyman.2001.324" rid="pandas.REF.heyman.2001.324">Heyman, et al., 2001</a>). This rate is comparable to that of a recent Danish population-based study that found a 0.84%-point prevalence of pediatric OCD (<a class="bibr" href="#pandas.REF.browne.2015.359" rid="pandas.REF.browne.2015.359">Browne, et al., 2015</a>). Interestingly, epidemiologic studies have found a bimodal distribution of the age-of-onset curve for OCD, with the first onset peak occurring at 9–10 years of age (SD +/- 2.5 yrs) and the second in the early twenties. Females predominate in post-pubertal cases, while boys outnumber girls by 2:1 in early-onset cases and 4:1 in PANDAS (<a class="bibr" href="#pandas.REF.schuyler.2023.89" rid="pandas.REF.schuyler.2023.89">Schuyler & Geller, 2023</a>).</p><p>Tic disorders do not have severity or impairment criteria and are defined only by the presence of “unvoluntary,” rapid, recurrent, and stereotyped movements or vocalizations (<a class="bibr" href="#pandas.REF.church.2003.602" rid="pandas.REF.church.2003.602">Church, Dale, Lees, Giovannoni, & Robertson, 2003</a>; <a class="bibr" href="#pandas.REF.eapen.2015.1431" rid="pandas.REF.eapen.2015.1431">Eapen & Robertson, 2015</a>). Tics are described as unvoluntary, rather than involuntary, because the movements and vocalizations can be suppressed by conscious thought and may be “suggestible”—increasing in frequency or intensity when the person thinks or talks about the tics and decreasing when the person is distracted or physically active (<a class="bibr" href="#pandas.REF.mcguire.2018.e1711" rid="pandas.REF.mcguire.2018.e1711">McGuire, et al., 2018</a>). Like OCD, tic disorders are reported to affect more boys than girls, and to peak in frequency between 8–10 years of age, with nearly all tics starting before adolescence. Prevalence rates are difficult to establish for tic disorders because transient tics do not persist long enough to be counted and simple tics may go unrecognized (e.g., a short-lived throat clearing tic is blamed on allergies). Despite these limitations, there is general agreement that tic disorders are common, particularly among grade-school aged children, reportedly affecting from 8% to 24% of pediatric populations (<a class="bibr" href="#pandas.REF.cubo.2011.100" rid="pandas.REF.cubo.2011.100">Cubo, et al., 2011</a>; <a class="bibr" href="#pandas.REF.gadow.2002.330" rid="pandas.REF.gadow.2002.330">Gadow, Nolan, Sprafkin, & Schwartz, 2002</a>; <a class="bibr" href="#pandas.REF.linazasoro.2006.2106" rid="pandas.REF.linazasoro.2006.2106">Linazasoro, Van Blercom, & de Zárate, 2006</a>; <a class="bibr" href="#pandas.REF.snider.2002.331" rid="pandas.REF.snider.2002.331">Snider, et al., 2002</a>). The wide range of reported frequencies may be partially explained by methodological variations among investigations, such as differences in the timing of observations and the age of the sample studied. For instance, Selling observed that tic frequency tends to increase during or following infections (<a class="bibr" href="#pandas.REF.selling.1929.1163" rid="pandas.REF.selling.1929.1163">Selling, 1929</a>). Snider, et al. conducted monthly in-person classroom observations of 553 children (aged 5–12 years) and reported that the monthly prevalence ranged from 3.2% to 9.6%, with the cumulative rate of prevalence at 24.4% over a seven-month observation period from November–June (<a class="bibr" href="#pandas.REF.snider.2002.331" rid="pandas.REF.snider.2002.331">Snider, et al., 2002</a>). Of interest, the highest rates were seen during the winter months of November through February, when <i>S. pyogenes</i> infections were most frequent in the community (<a class="bibr" href="#pandas.REF.snider.2002.331" rid="pandas.REF.snider.2002.331">Snider, et al., 2002</a>). The age of the population studied is also important: in a large study that included 3006 school children, the percentage with motor or vocal tics was 22.3% for preschool children, 7.8% for elementary school, and 3.4% for secondary school, with a male/female ratio of 3.8/1 in the elementary school group and 6.1/1 for the secondary school group (<a class="bibr" href="#pandas.REF.gadow.2002.330" rid="pandas.REF.gadow.2002.330">Gadow, Nolan, Sprafkin, & Schwartz, 2002</a>).</p><p>The phenomenology of OCD and tic disorders is of interest to the clinician striving to make an accurate diagnosis of PANDAS (<a class="bibr" href="#pandas.REF.gabbay.2008.273" rid="pandas.REF.gabbay.2008.273">Gabbay, et al., 2008</a>). Tics are described as “simple” if they involve a single movement/vocalization such eye-blinking, shoulder shrugs, or throat-clearing; and as “complex” if the tic is manifest as a combination of several motor and/or vocal tics (eye-blinking accompanied by facial grimacing and followed by a neck stretch). Some complex tics have a specific pattern, (e.g., stepping in a square and then touching one knee to the ground), which makes them indistinguishable from a compulsive ritual of OCD. Further, complex tics are often driven by a “premonitory urge” which may overlap the phenomenology of OCD-related compulsions (<a class="bibr" href="#pandas.REF.nespoli.2018.e0196515" rid="pandas.REF.nespoli.2018.e0196515">Nespoli, Rizzo, Boeckers, Schulze, & Hengerer, 2018</a>). This is particularly true in early-onset cases, where compulsive rituals are typically driven by an irresistible urge to perform the behavior rather than being triggered by a specific obsessional thought. This clinical overlap makes it clear that OCD and tic disorders are not dichotomous entities. Instead, tics and OCD symptoms lie along a continuum with pure obsessions at one end, simple motor tics (like an eyeblink) at the other end, and compulsions and complex tics overlapping in-between. Thus, it is not surprising that more than two-thirds of children with OCD also have tics, and 30-50% of children presenting with a tic disorder will be found to have obsessive-compulsive symptoms (<a class="bibr" href="#pandas.REF.swedo.1989.335" rid="pandas.REF.swedo.1989.335">Swedo, Rapoport, Leonard, Lenane, & Cheslow, 1989</a>). Attention deficit hyperactivity disorder (ADHD) is another common comorbidity of both OCD and tic disorders, particularly when symptoms start in early childhood.</p><div id="pandas.Basal_Ganglia_Involvement_and_Pat"><h3>Basal Ganglia Involvement and Pathology in OCD and PANDAS</h3><p>The triad of OCD, tics, and ADHD points to the basal ganglia as the primary site of pathology. The basal ganglia comprise a set of subcortical nuclei that include the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra. Their functional connections to several cortical regions have led to the conceptualization of the cortico-striatal (basal ganglia in humans)-thalamo-cortical (CBGTC) circuits (<a class="bibr" href="#pandas.REF.alexander.1986.357" rid="pandas.REF.alexander.1986.357">Alexander, DeLong, & Strick, 1986</a>). The function of these parallel, segregated feedback circuits is to control and select goal-directed motor, cognitive, and motivational behavior. They are also involved in inhibitory control (<a class="bibr" href="#pandas.REF.aron.2007.3743" rid="pandas.REF.aron.2007.3743">Aron, Behrens, Smith, Frank, & Poldrack, 2007</a>) and habit formation (<a class="bibr" href="#pandas.REF.gabbay.2008.273" rid="pandas.REF.gabbay.2008.273">Gabbay, et al., 2008</a>). Neuropsychological evaluations, structural and functional imaging studies, neurotransmitter investigations, and treatment trials have repeatedly demonstrated abnormalities of the basal ganglia in OCD, tic disorders and ADHD, particularly among cases with the OCD-tics-ADHD triad (<a class="bibr" href="#pandas.REF.graybiel.2000.343" rid="pandas.REF.graybiel.2000.343">Graybiel & Rauch, 2000</a>; <a class="bibr" href="#pandas.REF.graybiel.2008.359" rid="pandas.REF.graybiel.2008.359">Graybiel, 2008</a>; <a class="bibr" href="#pandas.REF.menzies.2008.525" rid="pandas.REF.menzies.2008.525">Menzies, et al., 2008</a>). In PANDAS, phase-related abnormalities are seen in basal ganglia structure and function (<a class="bibr" href="#pandas.REF.vreeland.2023.69" rid="pandas.REF.vreeland.2023.69">Vreeland, et al., 2023</a>). During acute illness, MRI scans of PANDAS patients show enlargements of basal ganglia structures and normalization following recovery, with a particularly striking case shown in <a class="figpopup" href="/books/NBK607260/figure/pandas.F1/?report=objectonly" target="object" rid-figpopup="figpandasF1" rid-ob="figobpandasF1">Figure 1</a> (<a class="bibr" href="#pandas.REF.giedd.1996.913" rid="pandas.REF.giedd.1996.913">Giedd, Rapoport, Leonard, Richter, & Swedo, 1996</a>). Additionally, cerebral magnetic resonance images of children with presumed streptococcus-associated OCD and/or tics and healthy children, also had significantly larger average sizes of the caudate, putamen, and globus pallidus than healthy children (<a class="bibr" href="#pandas.REF.giedd.2000.281" rid="pandas.REF.giedd.2000.281">Giedd, Rapoport, Garvey, Perlmutter, & Swedo, 2000</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpandasF1" co-legend-rid="figlgndpandasF1"><a href="/books/NBK607260/figure/pandas.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figpandasF1" rid-ob="figobpandasF1"><img class="small-thumb" src="/books/NBK607260/bin/pandas-Image001.gif" src-large="/books/NBK607260/bin/pandas-Image001.jpg" alt="Figure 1. . MRI Brain Scan before and after treatment in 14-year-old boy with PANDAS." /></a><div class="icnblk_cntnt" id="figlgndpandasF1"><h4 id="pandas.F1"><a href="/books/NBK607260/figure/pandas.F1/?report=objectonly" target="object" rid-ob="figobpandasF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">MRI Brain Scan before and after treatment in 14-year-old boy with PANDAS. At symptomatic baseline (Before Treatment), head of caudate nucleus was 20% larger than expected for age, sex and weight. Following successful treatment with plasmapheresis, the <a href="/books/NBK607260/figure/pandas.F1/?report=objectonly" target="object" rid-ob="figobpandasF1">(more...)</a></p></div></div><p>Of note, some studies of young adult males with early-onset OCD and an episodic course (whose <i>S. pyogenes</i> history was not sufficient to classify them as PANDAS) revealed a decrease in caudate size (<a class="bibr" href="#pandas.REF.luxenberg.1988.1089" rid="pandas.REF.luxenberg.1988.1089">Luxenberg, et al., 1988</a>). Furthermore, a succeeding study demonstrated greater gray matter volume and reduced white matter volume in the basal ganglia of patients with PANDAS, as compared with controls (<a class="bibr" href="#pandas.REF.cabrera.2019.533" rid="pandas.REF.cabrera.2019.533">Cabrera, et al., 2019</a>). This outcome is similar to the brain atrophy observed with various autoimmune CNS disorders, such as in cognitive lupus and multiple sclerosis (<a class="bibr" href="#pandas.REF.liu.2018.8" rid="pandas.REF.liu.2018.8">Liu, et al., 2018</a>; <a class="bibr" href="#pandas.REF.simon.2006.679" rid="pandas.REF.simon.2006.679">Simon, 2006</a>). Further indication of brain abnormalities are demonstrated by positron emission tomography (PET) scans utilizing ligand-translocator protein (TSPO); a marker of activated microglia showed increased uptake in the bilateral caudate and bilateral lentiform nuclei in PANDAS patients during symptomatic periods and normalization following successful treatment with IVIG (<a class="bibr" href="#pandas.REF.kumar.2015.749" rid="pandas.REF.kumar.2015.749">Kumar, Williams, & Chugani, 2015</a>).</p><p>Neuropsychological testing of 26 children with PANDAS followed in the USF Clinic revealed abnormalities consistent with basal ganglia dysfunction, which included poor performance on tasks of neurocognitive and executive ability (Stroop Color-Word Interference Test), visuospatial memory (Rey-Osterreith Complex Figure) and fine motor speed (finger tapping) (<a class="bibr" href="#pandas.REF.lewin.2011.391" rid="pandas.REF.lewin.2011.391">Lewin, Storch, Mutch, & Murphy, 2011</a>). Hirschstritt, et al. found abnormalities of response suppression, another task evaluating executive functions, and Casey, et al. found abnormalities on the response selection task that were comparable between SC and PANDAS patients and separated them from those with TS or ADHD (<a class="bibr" href="#pandas.REF.casey.1994.75" rid="pandas.REF.casey.1994.75">Casey, Vauss, & Swedo, 1994</a>; <a class="bibr" href="#pandas.REF.casey.1997.374" rid="pandas.REF.casey.1997.374">Casey, et al., 1997</a>; <a class="bibr" href="#pandas.REF.hirschtritt.2009.179" rid="pandas.REF.hirschtritt.2009.179">Hirschtritt, et al., 2009</a>). Polysomnography (sleep studies) show that more than 80% of PANDAS patients have a failure to establish atony during rapid eye movement (REM) sleep, a finding that also pinpoints dysfunction to the basal ganglia (<a class="bibr" href="#pandas.REF.gaughan.2016.1027" rid="pandas.REF.gaughan.2016.1027">Gaughan, et al., 2016</a>). Microglia, the resident immune cells in the brain, become activated in response to inflammation and neuronal damage, and their activation in PANDAS may both result from and contribute to neuronal damage and inflammatory responses observed in the brain tissue (<a class="bibr" href="#pandas.REF.frick.2016.8606057" rid="pandas.REF.frick.2016.8606057">Frick & Pittenger, 2016</a>).</p></div><div id="pandas.Symptom_Course_and_Variability_in"><h3>Symptom Course and Variability in PANDAS, OCD, Tics, and ADHD</h3><p>The triad of OCD, tics, and ADHD is of particular interest to PANDAS, given how frequently they co-occur in the disorder. While PANDAS is characterized by a fulminant onset or worsening of symptoms, most children with the OCD-tics-ADHD triad have a gradual onset and a slowly evolving course. Attentional difficulties are usually the earliest symptom, often coming to attention at day-care or in preschool; tics begin between 5 and 8 years of age and OCD starts a bit later. In most cases, the onset of the individual symptoms is also gradual—for example, the child might have an occasional eyeblink tic that slowly progresses to become more frequent and intense, taking weeks, months, or even years for additional tics to be added and the tic disorder to become impairing (<a class="bibr" href="#pandas.REF.martino.2012.2137" rid="pandas.REF.martino.2012.2137">Martino, Cavanna, Robertson, & Orth, 2012</a>). Once established, tics exhibit a “waxing and waning” course, with symptoms getting better or worse without obvious precipitants in some cases; while in others, predictable improvements occur during periods when the child is distracted or busy and worsen during periods of inactivity or when stressed by psychosocial factors (<a class="bibr" href="#pandas.REF.corbett.2008.810" rid="pandas.REF.corbett.2008.810">Corbett, Mendoza, Baym, Bunge, & Levine, 2008</a>; <a class="bibr" href="#pandas.REF.lin.2010.684" rid="pandas.REF.lin.2010.684">Lin, et al., 2010</a>). Tics also can have patterned waxing-waning cycles, such as seasonal variation in which tics are problematic during fall and winter and less bothersome in spring and summer. Diurnal cycles are also common, with tics being worse in the evening than during morning hours (<a class="bibr" href="#pandas.REF.buse.2014.184" rid="pandas.REF.buse.2014.184">Buse, Kirschbaum, Leckman, Münchau, & Roessner, 2014</a>; <a class="bibr" href="#pandas.REF.corbett.2008.810" rid="pandas.REF.corbett.2008.810">Corbett, Mendoza, Baym, Bunge, & Levine, 2008</a>). ADHD symptoms have little variation over the course of a day, week, month or season, although the symptoms are obviously more impairing at times when focused attention and concentration are required. The overall variability of OCD symptoms is somewhere between the waxing-waning course of tic disorders and the sustained severity of ADHD symptoms. Obsessions and compulsions often seem to worsen in response to psychosocial stressors and improve in novel situations, such as the “DisneyWorld effect,” where obsessions and compulsions disappear for the first day or two of a family vacation. Unfortunately, the symptoms quickly return and families are then confronted with managing the child’s obsessional fears and compulsive rituals in the hotel, restaurants, and other locations. In such cases, the reappearance of previously problematic symptoms would not qualify as an “episodic” course. Nor would the waxing-waning variations in symptom severity that are typically seen in tic disorders and OCD.</p><p>By definition, an episodic course of illness has distinct phases, with a high-severity interval followed by an interlude of no/low symptoms and then another high-severity episode; i.e., a relapsing-remitting course. The relapsing-remitting course characteristic of PANDAS is distinctly different from the fluctuating course of most OCD cases or the waxing-waning course that characterizes tic disorders—in those cases, symptom severity varies by 10–25% over time and not by 50–100%, as is seen in PANDAS. A sudden explosive onset or worsening of tics was reported by 42 of 80 (53%) of patients being followed in a tic disorders clinic; 15 (19%) had an infectious trigger with 9 (11%) of those being <i>S. pyogenes</i> (<a class="bibr" href="#pandas.REF.singer.2000.380" rid="pandas.REF.singer.2000.380">Singer, Giuliano, Zimmerman, & Walkup, 2000</a>). Prospective longitudinal studies of childhood-onset OCD found an episodic, relapsing-remitting course in one-quarter of the children and adolescents being followed in various clinical trials (<a class="bibr" href="#pandas.REF.leonard.1992.1244" rid="pandas.REF.leonard.1992.1244">Leonard, et al., 1992</a>). Most also had a history of an unusually abrupt onset of symptoms, which parents variously described as coming “out of the blue,” going “from 0 to 60 in two days,” or “being suddenly possessed by an OCD demon.” One parent reported that her daughter’s OCD “literally started overnight—she was fine when she went to bed and the next morning, her repeating rituals were so bad that she couldn’t get down the steps.” The acute, dramatic onset of these cases is clearly distinguishable from the gradual appearance of symptoms typically seen in OCD and tic disorders (<a class="bibr" href="#pandas.REF.snider.2002.331" rid="pandas.REF.snider.2002.331">Snider, et al., 2002</a>; <a class="bibr" href="#pandas.REF.swedo.1989.335" rid="pandas.REF.swedo.1989.335">Swedo, Rapoport, Leonard, Lenane, & Cheslow, 1989</a>; <a class="bibr" href="#pandas.REF.swedo.2004.907" rid="pandas.REF.swedo.2004.907">Swedo, Leonard, & Rapoport, 2004</a>). The PANDAS diagnosis can often be made by asking parents when the symptoms began—parents of children in the PANDAS subgroup are able to pinpoint the day/date (if not the time of day!) that their child’s symptoms began, while the gradual onset cases are unable to identify the timing closer than a month, season, or year.</p><p>Further research at NIMH revealed that a high proportion of children in the acute-onset subgroup had a preceding infectious illness, such as varicella, influenza, or a Group A streptococcal infection (<a class="bibr" href="#pandas.REF.allen.1995.307" rid="pandas.REF.allen.1995.307">Allen, Leonard, & Swedo, 1995</a>). Since then, the list of postulated precipitants has expanded to include mycoplasma pneumonia, <i>Borrelia burgdorferi</i> (<a class="bibr" href="#pandas.REF.m_ller.2004.119" rid="pandas.REF.m_ller.2004.119">Müller, et al., 2004</a>; <a class="bibr" href="#pandas.REF.riedel.1998.418" rid="pandas.REF.riedel.1998.418">Riedel, Straube, Schwatz, Wilske, & Müller, 1998</a>), and a number of viruses, including “common cold” viruses and SARS-CoV-2 (<a class="bibr" href="#pandas.REF.efe.2022.100074" rid="pandas.REF.efe.2022.100074">Efe, 2022</a>; <a class="bibr" href="#pandas.REF.leslie.2017.3" rid="pandas.REF.leslie.2017.3">Leslie, Kobre, Richmand, Guloksuz, & Leckman, 2017</a>; <a class="bibr" href="#pandas.REF.pavone.2021.e19" rid="pandas.REF.pavone.2021.e19">Pavone, et al., 2021</a>). An association between onset or exacerbation of neuropsychiatric symptoms and vaccinations has also been reported (<a class="bibr" href="#pandas.REF.cooperstock.2017.594" rid="pandas.REF.cooperstock.2017.594">Cooperstock, Swedo, Pasternack, & Murphy, 2017</a>; <a class="bibr" href="#pandas.REF.frankovich.2017.574" rid="pandas.REF.frankovich.2017.574">Frankovich, et al., 2017</a>; <a class="bibr" href="#pandas.REF.hoekstra.2005.285" rid="pandas.REF.hoekstra.2005.285">Hoekstra, Manson, Steenhuis, Kallenberg, & Minderaa, 2005</a>; <a class="bibr" href="#pandas.REF.krause.2010.359" rid="pandas.REF.krause.2010.359">Krause, et al., 2010</a>; <a class="bibr" href="#pandas.REF.mahony.2017.660" rid="pandas.REF.mahony.2017.660">Mahony, et al., 2017</a>; <a class="bibr" href="#pandas.REF.pallanti.2023.648" rid="pandas.REF.pallanti.2023.648">Pallanti & Di Ponzio, 2023</a>). Rapoport and the NIMH investigators chose post-streptococcal acute-onset cases for further study because of similarities between their clinical presentation and that of Sydenham chorea (SC), the neurologic manifestation of acute rheumatic fever (<a class="bibr" href="#pandas.REF.aron.1965.83" rid="pandas.REF.aron.1965.83">Aron, Freeman, & Carter, 1965</a>; <a class="bibr" href="#pandas.REF.ayoub.1966.946" rid="pandas.REF.ayoub.1966.946">Ayoub & Wannamaker, 1966</a>; <a class="bibr" href="#pandas.REF.cheadle.1889.821" rid="pandas.REF.cheadle.1889.821">Cheadle, 1889</a>; F., 1968; <a class="bibr" href="#pandas.REF.swedo.1994.1788" rid="pandas.REF.swedo.1994.1788">Swedo, 1994</a>; <a class="bibr" href="#pandas.REF.taranta.1989" rid="pandas.REF.taranta.1989">Taranta & Markowitz, 1989</a>). Both disorders have obsessive-compulsive symptoms (OCS) as part of their clinical presentation, and both have significant comorbidities, including emotional lability, ADHD, and other neuropsychiatric symptoms (<a class="bibr" href="#pandas.REF.swedo.1993.706" rid="pandas.REF.swedo.1993.706">Swedo, et al., 1993</a>; <a class="bibr" href="#pandas.REF.swedo.1994.1788" rid="pandas.REF.swedo.1994.1788">Swedo, 1994</a>; <a class="bibr" href="#pandas.REF.swedo.1997.110" rid="pandas.REF.swedo.1997.110">Swedo, et al., 1997</a>; <a class="bibr" href="#pandas.REF.swedo.1998.264" rid="pandas.REF.swedo.1998.264">Swedo, et al., 1998</a>). In addition, basal ganglia dysfunction/pathology is reported for both disorders (<a class="bibr" href="#pandas.REF.garvey.1998.413" rid="pandas.REF.garvey.1998.413">Garvey, Giedd, & Swedo, 1998</a>; <a class="bibr" href="#pandas.REF.teixeira.2021.913" rid="pandas.REF.teixeira.2021.913">Teixeira, Vasconcelos, Nunes, & Singer, 2021</a>). As early as 1976, Husby and colleagues had suggested that the cross-reactive antibodies found in SC sera might provide important information about the structures responsible for generating obsessions and compulsions (Husby, van de Rijn, Zabriskie, Abdin, & Williams Jr, 1976).</p><p>Familial and genetic studies also provided support for the utility of the SC medical model. Heritability estimates for OCD in children approximate 65%, which suggests a significant role for genetics, but leaves room for epigenetic and environmental factors (<a class="bibr" href="#pandas.REF.van_grootheest.2005.450" rid="pandas.REF.van_grootheest.2005.450">van Grootheest, Cath, Beekman, & Boomsma, 2005</a>). Childhood onset OCD has a higher family aggregation than adult OCD, with first-degree relatives of childhood-onset probands having a risk as high as 26%, while adult OCD relatives have only 12% (<a class="bibr" href="#pandas.REF.taylor.2011.1083" rid="pandas.REF.taylor.2011.1083">Taylor S. , 2011</a>). Family rates of autoimmune disorders are also increased, particularly among mothers of PANDAS probands (<a class="bibr" href="#pandas.REF.murphy.2002.356" rid="pandas.REF.murphy.2002.356">Murphy & Pichichero, 2002</a>; <a class="bibr" href="#pandas.REF.murphy.2010.243" rid="pandas.REF.murphy.2010.243">Murphy T. K., et al., 2010</a>; <a class="bibr" href="#pandas.REF.murphy.2012.314" rid="pandas.REF.murphy.2012.314">Murphy, Storch, Lewin, Edge, & Goodman, 2012</a>). Interestingly, when patients with acute rheumatic fever are the probands, their first-degree relatives have increased rates of obsessive-compulsive spectrum disorders (14.7% vs. 7.3% in controls, i=.028) as well as acute rheumatic fever (1.6% vs 3.6/1000 in Brazilian population) (<a class="bibr" href="#pandas.REF.hounie.2007.266" rid="pandas.REF.hounie.2007.266">Hounie, et al., 2007</a>). In regard to streptococcal infection with OCD and tics, a study of 261 individuals with tics and/or OCD found that 71 percent had evidence of group A streptococcal infection and the presence of obsessive-compulsive disorder (OCD) and tics was significantly associated with streptococcal infection status (overall Chi Square test p = 0.0087). After adjustment for multiple pairwise comparisons, subjects who were positive for streptococcus were more likely to have both tics and OCD (51%) than those who were negative for streptococcus (30%) (adjusted p = 0.0063) (<a class="bibr" href="#pandas.REF.cox.2015.76" rid="pandas.REF.cox.2015.76">Cox, et al., 2015</a>).</p></div></div><div id="pandas.Pandas_and_Sydenham_Chorea"><h2 id="_pandas_Pandas_and_Sydenham_Chorea_">Pandas and Sydenham Chorea</h2><p>As early as 1894, Sir William Osler described “perseverativeness of behavior” and emotional lability in children with SC (<a class="bibr" href="#pandas.REF.osler.1894" rid="pandas.REF.osler.1894">Osler, 1894</a>). In the 1920’s, <a class="bibr" href="#pandas.REF.hammes.1922.804" rid="pandas.REF.hammes.1922.804">Hammes (1922)</a> and <a class="bibr" href="#pandas.REF.ebaugh.1926.1083" rid="pandas.REF.ebaugh.1926.1083">Ebaugh (1926)</a> published detailed descriptions of the psychiatric and behavioral symptoms of SC, noting that “nearly all” children (90–98%) had new onset of emotional lability and other symptoms, including anxiety, anorexia, hallucinations, delusions, and obsessional fears (<a class="bibr" href="#pandas.REF.ebaugh.1926.1083" rid="pandas.REF.ebaugh.1926.1083">Ebaugh, 1926</a>; <a class="bibr" href="#pandas.REF.hammes.1922.804" rid="pandas.REF.hammes.1922.804">Hammes, 1922</a>). In a personal communication, Dr. Gene Stollerman recalled, “We saw obsessive-compulsive behaviors all the time on the lying-in wards (for ARF patients in New York and later in Chicago). The case I remember best was a little boy who kept sneaking out of bed to wash his hands at a sink in the corner—when the nurses tried to get him back into bed, he’d scream ‘but my hands have poison on them’.” Stollerman recalled that many of the children with Sydenham (chorea) were troubled by obsessions and compulsions. “We probably would have done more to treat those symptoms, if we weren’t so busy trying to keep them alive” (Telephone interview with SES in 2004). Wertheimer, Freeman, and colleagues reported that the SC psychiatric symptoms often persisted into adulthood, with many patients continuing to suffer from anxiety, psychosis (so-called “rheumatic schizophrenia”) and OCD (<a class="bibr" href="#pandas.REF.aron.1965.83" rid="pandas.REF.aron.1965.83">Aron, Freeman, & Carter, 1965</a>; <a class="bibr" href="#pandas.REF.wertheimer.1961.579" rid="pandas.REF.wertheimer.1961.579">Wertheimer, 1961</a>).</p><p>Based on these historical reports, Dr. Judy Rapoport led a series of investigations in the 1980’s to evaluate the utility ofSC as a “medical model” of OCD. The first investigation compared acute rheumatic fever (ARF) patients whose symptoms included chorea against those with ARF carditis alone, finding that two-thirds of the SC children (and none of the carditis sample) experienced the abrupt onset of obsessive-compulsive symptoms (OCS) in the weeks preceding onset of the chorea (<a class="bibr" href="#pandas.REF.swedo.1989.335" rid="pandas.REF.swedo.1989.335">Swedo, Rapoport, Leonard, Lenane, & Cheslow, 1989</a>). Two prospectively studied cohorts at NIMH and observations in an ARF clinic in São Paulo, confirmed and extended these findings by documenting that the rates of OCD increased from 60-70% at initial presentation of SC to 100% in children with multiple SC recurrences (<a class="bibr" href="#pandas.REF.asbahr.1998.1122" rid="pandas.REF.asbahr.1998.1122">Asbahr, et al., 1998</a>; <a class="bibr" href="#pandas.REF.asbahr.2005a.1073" rid="pandas.REF.asbahr.2005a.1073">Asbahr, et al., 2005a</a>; <a class="bibr" href="#pandas.REF.asbahr.2005b.159" rid="pandas.REF.asbahr.2005b.159">Asbahr, Ramos, Costa, & Sassi, 2005b</a>; <a class="bibr" href="#pandas.REF.garvey.1997.115" rid="pandas.REF.garvey.1997.115">Garvey & Swedo, 1997</a>; <a class="bibr" href="#pandas.REF.garvey.1998.413" rid="pandas.REF.garvey.1998.413">Garvey, Giedd, & Swedo, 1998</a>; <a class="bibr" href="#pandas.REF.swedo.1993.706" rid="pandas.REF.swedo.1993.706">Swedo S. E., et al., 1993</a>). These findings were further confirmed in subsequent studies that found increased rates of psychiatric symptoms in SC patients, and particularly for OCS and OCD, with Maia, et al., demonstrating that rates in SC patients were significantly higher than those found in rheumatic fever patients without chorea or healthy controls (<a class="bibr" href="#pandas.REF.dale.2005.785" rid="pandas.REF.dale.2005.785">Dale R. C., 2005</a>; <a class="bibr" href="#pandas.REF.d_azgrez.2004.810" rid="pandas.REF.d_azgrez.2004.810">Díaz-Grez, Lay-Son, del Barrio-Guerrero, & Vidal-González, 2004</a>; <a class="bibr" href="#pandas.REF.maia.2008.1251" rid="pandas.REF.maia.2008.1251">Maia, Cooney, & Peterson, 2008</a>; <a class="bibr" href="#pandas.REF.mercadante.2000.2036" rid="pandas.REF.mercadante.2000.2036">Mercadante, et al., 2000</a>; <a class="bibr" href="#pandas.REF.vasconcelos.2022.62" rid="pandas.REF.vasconcelos.2022.62">Vasconcelos, et al., 2022</a>). In all SC cases evaluated at NIMH, OCS were reported to have begun approximately 2 to 4 weeks before the onset or recurrence of chorea (<a class="bibr" href="#pandas.REF.perlmutter.1998.1592" rid="pandas.REF.perlmutter.1998.1592">Perlmutter, et al., 1998</a>). This was important for two reasons: first, it meant that the obsessions and compulsions were not just a “psychological reaction” to the SC impairments, since the OCS appeared before the child was known to have SC; and second, it permitted speculation that OCD might be a “forme fruste” of SC, sharing a common etiology and disease mechanism(s), but differing in the virulence “dose” required for symptom expression. The findings confirmed the utility of SC as a medical model for childhood-onset OCD and set the stage for discovery of the PANDAS subgroup (<a class="bibr" href="#pandas.REF.swedo.1994.1788" rid="pandas.REF.swedo.1994.1788">Swedo, 1994</a>; <a class="bibr" href="#pandas.REF.swedo.1998.264" rid="pandas.REF.swedo.1998.264">Swedo, et al., 1998</a>).</p><div id="pandas.PANDAS_Clinical_Presentation_Reco"><h3>PANDAS—Clinical Presentation, Recognition and Diagnosis</h3><p>Distinguishing the PANDAS subgroup from other presentations of OCD and tic disorders requires careful attention to the onset and clinical course of symptoms, as well as to the presence or absence of preceding <i>S. pyogenes</i> infections (<a class="bibr" href="#pandas.REF.swedo.1998.264" rid="pandas.REF.swedo.1998.264">Swedo, et al., 1998</a>). Onset must be acute, with symptoms rising from a stable premorbid baseline to maximum severity within 24–48 hours, and the clinical course must be relapsing-remitting, in which the symptomatic period is followed by complete remission of symptoms; or, if a recurrence happens before the child has returned to their premorbid baseline, there must be a distinct and clinically significant increase in symptom severity and functional impairments between phases. To meet criteria for the PANDAS subgroup (in comparison to PANS), the acute onset and at least one exacerbation of neuropsychiatric symptoms must be “associated with a streptococcal infection”—that is, the neuropsychiatric symptoms must follow an infection with, or close exposure to, a documented Group A streptococcal (<i>S. pyogenes</i>) infection.</p><p>Because <i>S. pyogenes</i> infections are ubiquitous among grade-school aged children, and a small fraction of children can harbor <i>S. pyogenes</i> for extended periods (asymptomatic infections or carrier status), a single association between <i>S. pyogenes</i> and symptom onset/exacerbation could occur by chance alone and be a spurious finding (<a class="bibr" href="#pandas.REF.kaplan.1980.337" rid="pandas.REF.kaplan.1980.337">Kaplan, 1980</a>; <a class="bibr" href="#pandas.REF.pichichero.1999b.624" rid="pandas.REF.pichichero.1999b.624">Pichichero, et al., 1999b</a>; <a class="bibr" href="#pandas.REF.shaikh.2010.e557" rid="pandas.REF.shaikh.2010.e557">Shaikh, Leonard, & Martin, 2010</a>). Actually, in northern climates during winter months, up to 30% of school children were reported to harbor <i>S. pyogenes</i> without symptoms. Krause, et al. found that some children carried <i>S. pyogenes</i> in their throats for at least a year (<a class="bibr" href="#pandas.REF.krause.2002.215" rid="pandas.REF.krause.2002.215">Krause, 2002</a>).</p><p>Therefore, the research criteria for PANDAS require at least two symptom exacerbations, such as onset and subsequent relapse, with evidence of a preceding <i>S. pyogenes</i> infection or exposure (<a class="bibr" href="#pandas.REF.swedo.1998.264" rid="pandas.REF.swedo.1998.264">Swedo, et al., 1998</a>; <a class="bibr" href="#pandas.REF.swedo.2004.907" rid="pandas.REF.swedo.2004.907">Swedo, Leonard, & Rapoport, 2004</a>). Since this requirement precludes a diagnosis of PANDAS at initial presentation, clinicians and research groups often assign a provisional diagnosis of PANDAS when there is evidence of a prior <i>S. pyogenes</i> infection. They subsequently monitor the child to determine if future exacerbations are also triggered by <i>S. pyogenes</i>. This can be done by obtaining a throat culture and/or perianal culture (as clinically indicated) and conducting serial anti-<i>S. pyogenes</i> titers during OCD/tic exacerbations. Since 2012, when Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) was added to the diagnostic repertoire (<a class="bibr" href="#pandas.REF.swedo.2012.113" rid="pandas.REF.swedo.2012.113">Swedo, Leckman, & Rose, 2012</a>), clinicians have had the additional option of reserving the PANDAS diagnosis for children meeting full research criteria and using the PANS criteria to characterize new onset cases (<a class="bibr" href="#pandas.REF.chang.2015.3" rid="pandas.REF.chang.2015.3">Chang, et al., 2015</a>; <a class="bibr" href="#pandas.REF.murphy.2014.353" rid="pandas.REF.murphy.2014.353">Murphy, Gerardi, & Leckman, 2014</a>; <a class="bibr" href="#pandas.REF.swedo.2017.562" rid="pandas.REF.swedo.2017.562">Swedo, Frankovich, & Murphy, 2017</a>; <a class="bibr" href="#pandas.REF.vreeland.2023.69" rid="pandas.REF.vreeland.2023.69">Vreeland, et al., 2023</a>). The full diagnostic criteria for PANDAS and PANS are presented in <a class="figpopup" href="/books/NBK607260/figure/pandas.F2/?report=objectonly" target="object" rid-figpopup="figpandasF2" rid-ob="figobpandasF2">Figure 2</a><b>.</b></p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpandasF2" co-legend-rid="figlgndpandasF2"><a href="/books/NBK607260/figure/pandas.F2/?report=objectonly" target="object" title="Figure 2. " class="img_link icnblk_img figpopup" rid-figpopup="figpandasF2" rid-ob="figobpandasF2"><img class="small-thumb" src="/books/NBK607260/bin/pandas-Image002.gif" src-large="/books/NBK607260/bin/pandas-Image002.jpg" alt="Figure 2. . Diagnostic criteria for PANDAS and PANS." /></a><div class="icnblk_cntnt" id="figlgndpandasF2"><h4 id="pandas.F2"><a href="/books/NBK607260/figure/pandas.F2/?report=objectonly" target="object" rid-ob="figobpandasF2">Figure 2. </a></h4><p class="float-caption no_bottom_margin">Diagnostic criteria for PANDAS and PANS. From (Swedo, et al., 1998; Swedo, Leonard, & Rapoport, 2004; Swedo, Leckman, & Rose, 2012). </p></div></div><p>The diagnostic criteria for PANS emphasize the importance of the concomitant onset of symptoms in multiple neuropsychiatric domains—behavioral, emotional, cognitive, sensory-motor, and somatic. In retrospect, the presence of multiple comorbidities also distinguished the first PANDAS cohort from the larger group of patients with gradual onset of OCD and tic disorders (<a class="bibr" href="#pandas.REF.swedo.1998.264" rid="pandas.REF.swedo.1998.264">Swedo, et al., 1998</a>). The most common comorbidities, meaning symptoms present along with tics and OCD, which have been observed (percentage of total patients evaluated in the two IVIg and other clinical trials at the National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH) in Bethesda, MD, USA, and described as seen by doctors (Drs. S. Swedo, S. J. Perlmutter, P. Grant, L. Snider, M. Garvey, and others) in PANDAS patients evaluated and include: separation anxiety (92%), hyperactivity or inattentiveness (92%), behavioral regression (63%), deteriorated school performance (60%), dysgraphia (44%), sensory hypersensitivities (44%), violent images or hallucinations (27%), personality changes (54%), separation anxiety (46%), nightmares (18%), bedtime rituals (50%), deterioration in handwriting (36%), oppositional behaviors (32%), and motoric hyperactivity (50%). Somatic symptoms were also quite common in PANDAS patients, particularly urinary urgency, frequency, and secondary enuresis (52%) (<a class="bibr" href="#pandas.REF.murphy.2002.356" rid="pandas.REF.murphy.2002.356">Murphy & Pichichero, 2002</a>; <a class="bibr" href="#pandas.REF.prato.2021.746639" rid="pandas.REF.prato.2021.746639">Prato, et al., 2021</a>; <a class="bibr" href="#pandas.REF.swedo.2015.26" rid="pandas.REF.swedo.2015.26">Swedo, et al., 2015</a>). Sleep difficulties (71%) such as insomnia, restless sleep, and rapid eye movement (REM) sleep abnormalities on polysomnography (80%) are also prevalent in both PANDAS and PANS (<a class="bibr" href="#pandas.REF.gagliano.2021.1209" rid="pandas.REF.gagliano.2021.1209">Gagliano, et al., 2021</a>; <a class="bibr" href="#pandas.REF.gaughan.2016.1027" rid="pandas.REF.gaughan.2016.1027">Gaughan, et al., 2016</a>). The clinical presentation of PANDAS and PANS has been consistently complex across various clinical and research samples, demonstrating striking similarities across different sites (<a class="bibr" href="#pandas.REF.colvin.2021.90" rid="pandas.REF.colvin.2021.90">Colvin, et al., 2021</a>; <a class="bibr" href="#pandas.REF.gamucci.2019.305" rid="pandas.REF.gamucci.2019.305">Gamucci, et al., 2019</a>; <a class="bibr" href="#pandas.REF.johnson.2019.175" rid="pandas.REF.johnson.2019.175">Johnson, et al., 2019</a>; <a class="bibr" href="#pandas.REF.leckman.2011.108" rid="pandas.REF.leckman.2011.108">Leckman, et al., 2011</a>; <a class="bibr" href="#pandas.REF.murphy.2002.356" rid="pandas.REF.murphy.2002.356">Murphy & Pichichero, 2002</a>; <a class="bibr" href="#pandas.REF.swedo.2015.26" rid="pandas.REF.swedo.2015.26">Swedo, et al., 2015</a>). For example, Bernstein and colleagues compared PANDAS cases with non-PANDAS OCD and observed higher rates of separation anxiety, urinary urgency, hyperactivity, impulsivity, deterioration in handwriting, decline in school performance, and increased severity of motor and vocal tics (<a class="bibr" href="#pandas.REF.bernstein.2010.333" rid="pandas.REF.bernstein.2010.333">Bernstein, Victor, Pipal, & Williams, 2010</a>). A 2015 report compared comorbidities observed among PANDAS patients evaluated at NIMH with those seen in two clinical practices (Hinsdale, IL, and Bethesda, MD), and found comparable rates for anxiety (73–92%); emotional lability and/or depression (66–94%); sensory or motor abnormalities (77–97%); behavioral (developmental) regression (60–69%); irritability, aggression and/or severely oppositional behaviors (26–50%); and somatic signs and symptoms, including sleep disturbances, enuresis, or urinary frequency (83–98%) (<a class="bibr" href="#pandas.REF.swedo.2015.26" rid="pandas.REF.swedo.2015.26">Swedo, et al., 2015</a>).</p><p>Restrictions of intake of food and fluids are reported to occur in 20%–50% of PANDAS cases, with many meeting DSM-5 criteria for Avoidant Restrictive Food Intake Disorder (ARFID; DSM code 307.59) and some being affected so severely that tube feedings and/or IV hydration are required (<a class="bibr" href="#pandas.REF.toufexis.2015.48" rid="pandas.REF.toufexis.2015.48">Toufexis, et al., 2015</a>). The acute-onset of eating restrictions following <i>S. pyogenes</i> infections had gone largely unnoticed until Mae Sokol and colleagues reported a series of cases of post-<i>S. pyogenes</i> anorexia nervosa (<a class="bibr" href="#pandas.REF.sokol.1997.1128" rid="pandas.REF.sokol.1997.1128">Sokol & Gray, 1997</a>; <a class="bibr" href="#pandas.REF.toufexis.2015.48" rid="pandas.REF.toufexis.2015.48">Toufexis, et al., 2015</a>). Psychotic symptoms, including delusions and both visual and auditory hallucinations, are not uncommon in PANDAS cases (14—27%) (<a class="bibr" href="#pandas.REF.murphy.2014.353" rid="pandas.REF.murphy.2014.353">Murphy, Gerardi, & Leckman, 2014</a>; <a class="bibr" href="#pandas.REF.murphy.2015.14" rid="pandas.REF.murphy.2015.14">Murphy, et al., 2015</a>; <a class="bibr" href="#pandas.REF.swedo.1998.264" rid="pandas.REF.swedo.1998.264">Swedo, et al., 1998</a>). Interestingly, feeding restrictions and psychotic symptoms were noted in some of the early case descriptions of SC patients hospitalized on “lying in wards” in the 1920’s. For example, Hammes documented a case of a young girl hospitalized for SC who experienced periods of intense fear, particularly when alone in the dark. She had visual hallucinations, including seeing mice and moving objects in her room, and even witnessed a man climbing through the window, causing her to scream in fear (<a class="bibr" href="#pandas.REF.hammes.1922.804" rid="pandas.REF.hammes.1922.804">Hammes, 1922</a>). Further, she believed that her food was “poisoned” and had to be tube-fed for ten days because she refused to eat or drink (<a class="bibr" href="#pandas.REF.punukollu.2016.16" rid="pandas.REF.punukollu.2016.16">Punukollu, Mushet, Linney, Hennessy, & Morton, 2016</a>).</p><p>The overlap between the psychiatric symptoms of SC and those of PANDAS means that clinical history is insufficient to separate the two disorders and a differential diagnosis must be made on the basis of the neurological exam (<a class="bibr" href="#pandas.REF.murphy.2000.851" rid="pandas.REF.murphy.2000.851">Murphy, Goodman, Ayoub, & Voeller, 2000</a>). Thus, it is important that clinicians are aware of the differences between the two neurological presentations. Sydenham chorea is described as a “hyperkinetic (or dyskinetic) disorder” defined by the presence of involuntary, purposeless, brief, abrupt, irregular, unpredictable, non-stereotyped movements. The movements are present at rest and may increase with voluntary movements of the affected area or as “overflow” from other areas. The adventitious movements impair functioning, including activities of daily living, like writing and drawing, holding a drinking cup, or even brushing hair or teeth (<a class="bibr" href="#pandas.REF.dale.2005.785" rid="pandas.REF.dale.2005.785">Dale, 2005</a>; <a class="bibr" href="#pandas.REF.dale.2010.739" rid="pandas.REF.dale.2010.739">Dale, et al., 2010</a>; <a class="bibr" href="#pandas.REF.taranta.1956.170" rid="pandas.REF.taranta.1956.170">Taranta & Stollerman, 1956</a>; <a class="bibr" href="#pandas.REF.teixeira.2021.913" rid="pandas.REF.teixeira.2021.913">Teixeira, Vasconcelos, Nunes, & Singer, 2021</a>). The choreatic movements primarily affect the limbs and face, but can cause truncal instability as well. Swallowing difficulties (dysphagia) can occur in SC due to the inter-related functions of voluntary and involuntary muscles involved in swallowing. SC patients may also exhibit “choreoathetoid movements” that have features of both chorea and athetosis, (slower, writhing, or twisting movements that primarily affect the hands and feet). Chorea is usually bilateral, but hemichorea can occur in 7 to 54% of cases (<a class="bibr" href="#pandas.REF.dale.2005.785" rid="pandas.REF.dale.2005.785">Dale, 2005</a>). In addition to these adventitious movements, SC is characterized by hypotonia (in extreme cases proceeding to “chorea molle,” in which the patient is unable to rise from a bed or even lift their head from the pillow) and motor impersistence, which produces the pathognomonic sign of SC—“Milkmaid’s grip” in which the child alternately squeezes and releases your fingers/hand as they try to maintain a hold or shake your hand (<a class="bibr" href="#pandas.REF.garvey.1997.115" rid="pandas.REF.garvey.1997.115">Garvey & Swedo, 1997</a>; <a class="bibr" href="#pandas.REF.swedo.1994.1788" rid="pandas.REF.swedo.1994.1788">Swedo S. E., 1994</a>; <a class="bibr" href="#pandas.REF.taranta.1956.170" rid="pandas.REF.taranta.1956.170">Taranta & Stollerman, 1956</a>). Motor impersistence also contributes to a “Jack-in-the-Box (or snake-like) tongue” where the tongue darts in and out of the mouth as the child tries to maintain tongue protrusion. Hung-up reflexes are often present in SC and may provide an additional diagnostic clue during the neurological examination (<a class="bibr" href="#pandas.REF.dale.2005.785" rid="pandas.REF.dale.2005.785">Dale, 2005</a>).</p><p>Clinicians are urged to conduct a careful neurological examination to exclude the presence of chorea or choreoathetoid movements before determining that a child has PANDAS. If any chorea is present, a diagnosis of SC should be made and the child should be evaluated for other signs of acute rheumatic fever, such as carditis (reportedly present in 30%–70% of SC patients), polyarthritis, erythema marginatum and erythema nodosum. Please note that tics and “compulsive utterances” are not uncommon in SC, requiring careful attention to the speed of the movement, its relationship to voluntary movements, and rhythmicity to assign the right descriptive label (<a class="bibr" href="#pandas.REF.cardoso.1999.805" rid="pandas.REF.cardoso.1999.805">Cardoso, Vargas, Oliveira, Guerra, & Amaral, 1999</a>; <a class="bibr" href="#pandas.REF.creak.1937.93" rid="pandas.REF.creak.1937.93">Creak & Guttmann, 1937</a>). The differential diagnosis of SC includes atypical seizures, cerebrovascular accidents, collagen vascular diseases such as SLE or periarteritis nodosa, drug intoxication, familial choreas (including Huntington’s disease, familial chorea with acanthyocytosis, ataxia telangiectasia and others), hormonally induced chorea (which are typically estrogen-induced, so may be seen with oral contraceptives or during pregnancy—SC that recurs during pregnancy is known as chorea gravidarum), hyperthyroidism, hypoparathyroidism, Lyme disease, and Wilson’s disease (<a class="bibr" href="#pandas.REF.dale.2010.739" rid="pandas.REF.dale.2010.739">Dale, et al., 2010</a>; <a class="bibr" href="#pandas.REF.swedo.1994.1788" rid="pandas.REF.swedo.1994.1788">Swedo, 1994</a>). Since SC is a “diagnosis of exclusion,” the conditions in the differential diagnosis should be ruled out before an SC diagnosis is assigned.</p><p>PANDAS is also a diagnosis of exclusion and should not be considered until the possibility of SC or another disorder has been eliminated. The neurological exam of a child with PANDAS may reveal the presence of tics and/or choreiform movements. Tics are reported to co-occur with SC in 4% to 73% of cases, so their presence or absence cannot serve to distinguish SC from PANDAS (<a class="bibr" href="#pandas.REF.cardoso.1999.805" rid="pandas.REF.cardoso.1999.805">Cardoso, Vargas, Oliveira, Guerra, & Amaral, 1999</a>; <a class="bibr" href="#pandas.REF.mercadante.2000.2036" rid="pandas.REF.mercadante.2000.2036">Mercadante, et al., 2000</a>). Choreiform movements were first described by Touwen in 1979 as “fine piano-playing movements of the fingers that are elicited in the stressed posture of a Romberg stance” (<a class="bibr" href="#pandas.REF.touwen.1979" rid="pandas.REF.touwen.1979">Touwen, 1979</a>). They are thought to represent a lack of inhibitory control, as they can be a normal developmental sign until approximately 6 years of age. They are also present in many children with PANDAS during the acute phase of illness, regardless of their age. Although choreiform movements sound like they should be akin to chorea, they are not. Choreiform movements are easily distinguished from the choreatic and choreoathetoid movements of SC, as they are not present at rest, do not interfere with voluntary movements, and do not cause functional impairments (with the possible exception of producing deteriorations in handwriting/drawing skills). In fact, the initial part of the name “choreiform” may be the only feature in common between these adventitious movements and those of Sydenham chorea.</p><p>In summary, the PANDAS subgroup of patients can be distinguished from the larger group of patients with OCD or tic disorders by the clinical history—PANDAS patients have an unusually fulminant onset of OCS accompanied by multiple symptoms in the behavioral, emotional, sensory-motor, and somatic domains, and <i>S. pyogenes</i> infection or exposure precedes symptom onset and most, if not all, subsequent symptom exacerbations. PANDAS can be distinguished from SC by neurological examination. PANDAS is diagnosed only when there is a complete absence of the choreatic or choreoathetoid movements of SC. Choreiform movements may be present in Romberg stance but are otherwise not noticeable, do not interfere with voluntary movements, and do not impair functioning. Further information about the diagnostic evaluation of acute-onset OCD/tics is reviewed in the following sources: (<a class="bibr" href="#pandas.REF.chang.2015.3" rid="pandas.REF.chang.2015.3">Chang, et al., 2015</a>; <a class="bibr" href="#pandas.REF.swedo.2004.907" rid="pandas.REF.swedo.2004.907">Swedo, Leonard, & Rapoport, 2004</a>; <a class="bibr" href="#pandas.REF.swedo.2012.113" rid="pandas.REF.swedo.2012.113">Swedo, Leckman, & Rose, 2012</a>).</p><p>No discussion of the clinical presentation of PANDAS would be complete without considering its relationship to acute rheumatic fever (ARF). By definition, a diagnosis of PANDAS cannot be made if there is any evidence of ARF, whether it be SC, carditis, or arthritis. Perhaps this is a major reason for the debate on the role of <i>S. pyogenes</i> and shared pathogenesis with SC in PANDAS. However, with that said, there is strong evidence that both SC and PANDAS share similar antineuronal autoantibodies that connect PANDAS with ARF (<a class="bibr" href="#pandas.REF.chain.2020.564" rid="pandas.REF.chain.2020.564">Chain, et al., 2020</a>; <a class="bibr" href="#pandas.REF.dale.2012.3453" rid="pandas.REF.dale.2012.3453">Dale, et al., 2012</a>; <a class="bibr" href="#pandas.REF.kirvan.2003.914" rid="pandas.REF.kirvan.2003.914">Kirvan, Swedo, Heuser, & Cunningham, 2003</a>; <a class="bibr" href="#pandas.REF.kirvan.2006a.173" rid="pandas.REF.kirvan.2006a.173">Kirvan, Swedo, Snider, & Cunningham, 2006a</a>; <a class="bibr" href="#pandas.REF.kirvan.2006b.21" rid="pandas.REF.kirvan.2006b.21">Kirvan, Swedo, Kurahara, & Cunningham, 2006b</a>; Menendez, 2024). Menendez, et al. contains information regarding the differences between the antineuronal autoantibodies in PANDAS vs SC and defines the two diseases serologically.</p><p>With rheumatic carditis as an exclusionary criterion, it is not surprising that cardiologic evaluations of children in the PANDAS subgroup have failed to find pathological valvular regurgitations. For example, in a study by Snider, et al., 60 PANDAS patients underwent echocardiogram evaluation at entry into NIMH research. Out of these patients, 32 (53%) exhibited trace or physiologic mitral regurgitation. Additionally, one patient had mild mitral regurgitation with normal leaflet morphology, one had trace aortic regurgitation, and one had thickened mitral valve leaflets with only trace mitral regurgitation. Long-term follow-up evaluations, averaging 3.8 years, were conducted on 20 of these subjects, revealing that 11 individuals continued to demonstrate non-impairing mitral regurgitation (<a class="bibr" href="#pandas.REF.snider.2004.e748" rid="pandas.REF.snider.2004.e748">Snider, Sachdev, MacKaronis, St Peter, & Swedo, 2004</a>). Segarra and Murphy performed cardiologic evaluations on 10 children with PANDAS and found no evidence of mitral or aortic insufficiency/regurgitation, but did see minimal (physiologic) tricuspid regurgitation and/or pulmonary insufficiency in 8 subjects (<a class="bibr" href="#pandas.REF.segarra.2008.603" rid="pandas.REF.segarra.2008.603">Segarra & Murphy, 2008</a>). Cardona and colleagues used four-color Doppler echocardiography to evaluate 48 patients with tic disorders plus signs of recent or intercurrent exposure to streptococcal antigens (Tics+Strep group) and compared them against 18 age-matched tic patients without evidence of streptococcal exposure (Tics-noStrep group). 26 (54.3%) of the Tics+Strep patients had trivial/mild mitral regurgitation, 1 patient had mitral valve prolapse, and 1 showed kinking of the anterior mitral valve leaflet; in comparison, only four of the 18 (22.2%) children in the Tics-noStrep group showed any signs of mitral regurgitation. Of note, four of six children who met the criteria for PANDAS had evidence of mitral regurgitation. None of the abnormalities was hemodynamically significant, and in many cases, the insufficiency/regurgitation decreased over time (<a class="bibr" href="#pandas.REF.cardona.2004.186" rid="pandas.REF.cardona.2004.186">Cardona, et al., 2004</a>; <a class="bibr" href="#pandas.REF.cardona.2007.270" rid="pandas.REF.cardona.2007.270">Cardona, et al., 2007</a>). The authors interpreted their findings as indicating that patients with tic disorders, and particularly those who met the criteria for PANDAS, may develop post-streptococcal “silent” carditis similar to that seen in many SC cases (<a class="bibr" href="#pandas.REF.cardona.2007.270" rid="pandas.REF.cardona.2007.270">Cardona, et al., 2007</a>). It should be noted, however, that the rates in the Cardona study are comparable to frequencies of “physiologic” mitral valve regurgitation found in healthy children in other studies (<a class="bibr" href="#pandas.REF.thomson.2000.185" rid="pandas.REF.thomson.2000.185">Thomson, Allen, & Gibbs, 2000</a>). To date, an Italian center study is the only known report of auscultatory abnormalities in PANDAS (<a class="bibr" href="#pandas.REF.murciano.2019.395" rid="pandas.REF.murciano.2019.395">Murciano, et al., 2019</a>). They examined 30 children with PANDAS (one of whom was known to have Wolf-Parkinson-White syndrome) and found a cardiac systolic murmur in 17 patients (56.7%). Electrocardiograms showed sharp T waves in V1 and V2 derivations in one child, and echocardiograms showed that five had (ungraded) mitral valve insufficiency (16.7%). None of the abnormalities was considered to be clinically impairing, but the authors raised the possibility that PANDAS patients, like children with SC, might be at increased risk for developing ARF carditis in response to future <i>S. pyogenes</i> infections and recommended that PANDAS patients undergo cardiologic screening at disease onset and annually until puberty (<a class="bibr" href="#pandas.REF.murciano.2019.395" rid="pandas.REF.murciano.2019.395">Murciano, et al., 2019</a>).</p></div></div><div id="pandas.PANDAS_Studies_of_Etiology_and_Pa"><h2 id="_pandas_PANDAS_Studies_of_Etiology_and_Pa_">PANDAS—Studies of Etiology and Pathogenesis</h2><p>Although clinical evidence supports the role of <i>S. pyogenes</i> in the pathogenesis of PANDAS, similar to <i>S. pyogenes</i> involvement in SC, establishing an acceptance of the link with <i>S. pyogenes</i> with PANDAS remains a subject of debate. To determine the role of <i>S. pyogenes</i> in the etiology and pathophysiology of PANDAS, comprehensive evidence from epidemiologic surveys, clinical investigations, and basic/translational research studies is essential. It's noteworthy that many laboratory investigations related to PANDAS have been conducted in tandem with research on the pathophysiology of SC. These findings add credence to the comparability of clinical presentations in both PANDAS and SC. For a more detailed discussion, please refer to the chapter entitled “Post-Streptococcal Autoimmune Sequelae: Rheumatic Fever and Beyond.”</p><div id="pandas.The_Etiologic_Role_of_CrossReacti"><h3>The Etiologic Role of Cross-Reactive (Antineuronal) Antibodies</h3><p>Husby and colleagues were the first to demonstrate the presence of cross-reactive (or antineuronal) antibodies in serum samples from patients with SC (Husby, van de Rijn, Zabriskie, Abdin, & Williams Jr, 1976). These antibodies were presumed to have been a healthy immune response to the <i>S. pyogenes</i> infection, but became problematic because of “molecular mimicry” of the <i>S. pyogenes</i> bacteria. The <i>S. pyogenes</i> molecular mimics are proteins, lipoproteins, glycoproteins, and other epitopes that have molecular or conformational similarity to host antigens and which are displayed on the <i>S. pyogenes</i> cell wall to help it evade the human immune response (<a class="bibr" href="#pandas.REF.cunningham.2019" rid="pandas.REF.cunningham.2019">Cunningham M. W., 2019</a>). While molecular mimicry is crucial to the <i>S. pyogenes</i> bacteria’s survival, it is not beneficial to the human host and becomes pathological if and when the cross-reactive antibodies “see” the streptococcal-mimicked host epitopes and produce an inflammatory and autoantibody response against the host tissue. The most recent findings point to a strong N- acetyl-beta-D-glucosamine (GlcNAc) specific IgG2 antibody response against streptococcal and host antigens in ARF including the CSF in SC, and the GlcNAc-specific IgG2 response is significantly lower in children with uncomplicated streptococcal infections (<a class="bibr" href="#pandas.REF.kirvan.2023.919700" rid="pandas.REF.kirvan.2023.919700">Kirvan, et al., 2023</a>). GlcNAc-specific IgG2 hyperresponsiveness against the group A carbohydrate epitope GlcNAc may be an important biomarker of <i>S. pyogenes</i> ARF risk and sequelae but has yet to be investigated in PANDAS.</p><p>In the early investigation by Husby, et al., the cross-reactivity of autoantibodies from SC sera appeared to be directed primarily against neuronal tissue in the basal ganglia, including the caudate and subthalamic nuclei (Husby, van de Rijn, Zabriskie, Abdin, & Williams Jr, 1976). The SC autoantibodies differed from those of patients with juvenile rheumatoid arthritis (JRA) or systemic lupus erythematosus (SLE) in two important ways: they had greater reactivity against the neuronal tissue, and they were absorbed by <i>S. pyogenes</i> cell walls, membranes, and other cellular components (the JRA and SLE samples were not) which provided strong support for cross-reactivity (Husby, van de Rijn, Zabriskie, Abdin, & Williams Jr, 1976). Decades later, these findings were replicated and extended by Kirvan, et al., and others who again demonstrated reactivity of IgG from SC sera and cerebrospinal fluid (CSF) against basal ganglia structures, particularly against the caudate nuclei (<a class="bibr" href="#pandas.REF.kirvan.2003.914" rid="pandas.REF.kirvan.2003.914">Kirvan, Swedo, Heuser, & Cunningham, 2003</a>; <a class="bibr" href="#pandas.REF.kirvan.2006a.173" rid="pandas.REF.kirvan.2006a.173">Kirvan, Swedo, Snider, & Cunningham, 2006a</a>). Subsequent findings determined that antibodies from SC cases specifically targeted the human dopamine-2 receptor (D2R) (<a class="bibr" href="#pandas.REF.cox.2013.5524" rid="pandas.REF.cox.2013.5524">Cox, et al., 2013</a>; <a class="bibr" href="#pandas.REF.dale.2012.3453" rid="pandas.REF.dale.2012.3453">Dale, et al., 2012</a>), and provoked dopamine release in human neuronal cells (<a class="bibr" href="#pandas.REF.cox.2013.5524" rid="pandas.REF.cox.2013.5524">Cox, et al., 2013</a>; <a class="bibr" href="#pandas.REF.kirvan.2006a.173" rid="pandas.REF.kirvan.2006a.173">Kirvan, Swedo, Snider, & Cunningham, 2006a</a>). Moreover, Morshed and colleagues analyzed sera from patients with TS, SC, and a mixed group of autoimmune disorders. They observed serum antibody reactivity against various neural, nuclear, cytoskeletal, and streptococcal epitopes, and identified distinct patterns of reactivity that differentiated the three groups (<a class="bibr" href="#pandas.REF.morshed.2001.566" rid="pandas.REF.morshed.2001.566">Morshed, et al., 2001</a>). Dale and colleagues analyzed sera from children with post-streptococcal acute disseminated encephalomyelitis (ADEM) which identified anti-basal ganglia autoantibodies (<a class="bibr" href="#pandas.REF.dale.2001.588" rid="pandas.REF.dale.2001.588">Dale, et al., 2001</a>). Sera from children with PANDAS-like illnesses demonstrated the presence of antibodies that reacted against surface D2R (<a class="bibr" href="#pandas.REF.brimberg.2012.2076" rid="pandas.REF.brimberg.2012.2076">Brimberg, et al., 2012</a>; <a class="bibr" href="#pandas.REF.cox.2013.5524" rid="pandas.REF.cox.2013.5524">Cox, et al., 2013</a>; <a class="bibr" href="#pandas.REF.dale.2012.3453" rid="pandas.REF.dale.2012.3453">Dale, et al., 2012</a>). These observations led Dale and colleagues to categorize SC and PANDAS as an autoimmune basal ganglia encephalitis, and the autoimmunity observed in SC and PANDAS was associated with cross-reactive anti-<i>S. pyogenes</i> /anti-neuronal antibodies (<a class="bibr" href="#pandas.REF.dale.2012.3453" rid="pandas.REF.dale.2012.3453">Dale, et al., 2012</a>). Consequently, PANDAS does not require separation from SC, except as necessary for clinical practices, as both conditions can present as an autoimmune basal ganglia encephalitis associated with similar autoimmune responses and behavioral abnormalities (<a class="bibr" href="#pandas.REF.kirvan.2006a.173" rid="pandas.REF.kirvan.2006a.173">Kirvan, Swedo, Snider, & Cunningham, 2006a</a>). However, most recently, SC and PANDAS have been separated with PANDAS associated primarily with the D1R autoantibodies and neuropsychiatric behaviors and SC with the D2R autoantibodies and chorea or choreiform movements (<a class="bibr" href="#pandas.REF.menendez.2024" rid="pandas.REF.menendez.2024">Menendez, et al., 2024</a>).</p><p>Further investigations identified and characterized patient-derived monoclonal antibody (mAb)s originating from SC. The SC human mAb 24.3.1 reacted with neuronal cells, basal ganglia tissue, and neuronal autoantigens, and also promoted the activation of tyrosine hydroxylase activity in dopaminergic neurons (<a class="bibr" href="#pandas.REF.kirvan.2003.914" rid="pandas.REF.kirvan.2003.914">Kirvan, Swedo, Heuser, & Cunningham, 2003</a>). This effect was observed in immunological assays, in vitro and ex vivo experiments, human tissue staining, and following the intrathecal transfer of purified human mAb 24.3.1 into the brain of a Lewis rat (<a class="bibr" href="#pandas.REF.kirvan.2006a.173" rid="pandas.REF.kirvan.2006a.173">Kirvan, Swedo, Snider, & Cunningham, 2006a</a>; <a class="bibr" href="#pandas.REF.kirvan.2006b.21" rid="pandas.REF.kirvan.2006b.21">Kirvan, Swedo, Kurahara, & Cunningham, 2006b</a>) (<a class="figpopup" href="/books/NBK607260/figure/pandas.F3/?report=objectonly" target="object" rid-figpopup="figpandasF3" rid-ob="figobpandasF3">Figure 3</a>). Both the brain antigen-specific human mAbs and the autoantibodies from SC serum and cerebrospinal fluid (CSF) were found to induce calcium calmodulin-dependent protein kinase II (CaMKII) (<a class="bibr" href="#pandas.REF.brimberg.2012.2076" rid="pandas.REF.brimberg.2012.2076">Brimberg, et al., 2012</a>; <a class="bibr" href="#pandas.REF.kirvan.2003.914" rid="pandas.REF.kirvan.2003.914">Kirvan, Swedo, Heuser, & Cunningham, 2003</a>). CaMKII activation is known to be involved in the increase of tyrosine hydroxylase, an enzyme necessary for dopamine synthesis (<a class="bibr" href="#pandas.REF.lehmann.2006.17644" rid="pandas.REF.lehmann.2006.17644">Lehmann, Bobrovskaya, Gordon, Dunkley, & Dickson, 2006</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpandasF3" co-legend-rid="figlgndpandasF3"><a href="/books/NBK607260/figure/pandas.F3/?report=objectonly" target="object" title="Figure 3. " class="img_link icnblk_img figpopup" rid-figpopup="figpandasF3" rid-ob="figobpandasF3"><img class="small-thumb" src="/books/NBK607260/bin/pandas-Image003.gif" src-large="/books/NBK607260/bin/pandas-Image003.jpg" alt="Figure 3. . Sydenham’s chorea mAb 24." /></a><div class="icnblk_cntnt" id="figlgndpandasF3"><h4 id="pandas.F3"><a href="/books/NBK607260/figure/pandas.F3/?report=objectonly" target="object" rid-ob="figobpandasF3">Figure 3. </a></h4><p class="float-caption no_bottom_margin">Sydenham’s chorea mAb 24.3.1 induced increased levels of tyrosine hydroxylase in vivo. Chorea mAb 24.3.1 or isotype control were passively transferred into intracerebroventricular cannulated Lewis rats (Hilltop Lab Animals, Inc.) every day for <a href="/books/NBK607260/figure/pandas.F3/?report=objectonly" target="object" rid-ob="figobpandasF3">(more...)</a></p></div></div><p>Autoantibody-mediated neuronal cell signaling was shown to be induced by IgG antibodies in serum or cerebrospinal fluid from SC, and the presence of these signaling autoantibodies were associated with symptom severity (<a class="bibr" href="#pandas.REF.kirvan.2003.914" rid="pandas.REF.kirvan.2003.914">Kirvan, Swedo, Heuser, & Cunningham, 2003</a>; <a class="bibr" href="#pandas.REF.benpazi.2013.e73516" rid="pandas.REF.benpazi.2013.e73516">Ben-Pazi, Stoner, & Cunningham, 2013</a>). Removal of IgG from serum caused a loss of neuronal cell-signaling activity (<a class="bibr" href="#pandas.REF.brimberg.2012.2076" rid="pandas.REF.brimberg.2012.2076">Brimberg, et al., 2012</a>; <a class="bibr" href="#pandas.REF.kirvan.2003.914" rid="pandas.REF.kirvan.2003.914">Kirvan, Swedo, Heuser, & Cunningham, 2003</a>). In subsequent research, the investigators demonstrated that the SC sera and transgenic mice that expressed the human mAb 24.3.1 VH gene bound D2R transfected cells and induced downstream D2R-coupled G<sub>i/o</sub> G protein signaling (<a class="bibr" href="#pandas.REF.cox.2013.5524" rid="pandas.REF.cox.2013.5524">Cox, et al., 2013</a>). The human SC mAb 24.3.1 also induced excess dopamine release from human SKNSH cells (<a class="bibr" href="#pandas.REF.kirvan.2006a.173" rid="pandas.REF.kirvan.2006a.173">Kirvan, Swedo, Snider, & Cunningham, 2006a</a>) <b>(</b><a class="figpopup" href="/books/NBK607260/figure/pandas.F4/?report=objectonly" target="object" rid-figpopup="figpandasF4" rid-ob="figobpandasF4">Figure 4</a>). Furthermore, the expression of human-derived SC AAb V genes in B cells of transgenic (TG) mice revealed that antineuronal AAbs expressed in the blood of the mice targeted the basal ganglia and dopaminergic neurons in the Tg mice. Specifically, the affected areas included the ventral tegmental area (VTA) and the substantia nigra (<a class="figpopup" href="/books/NBK607260/figure/pandas.F5/?report=objectonly" target="object" rid-figpopup="figpandasF5" rid-ob="figobpandasF5">Figure 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpandasF4" co-legend-rid="figlgndpandasF4"><a href="/books/NBK607260/figure/pandas.F4/?report=objectonly" target="object" title="Figure 4. " class="img_link icnblk_img figpopup" rid-figpopup="figpandasF4" rid-ob="figobpandasF4"><img class="small-thumb" src="/books/NBK607260/bin/pandas-Image004.gif" src-large="/books/NBK607260/bin/pandas-Image004.jpg" alt="Figure 4. . Tritiated dopamine release by SKNSH human neuronal cells treated with (A) Sydenham’s chorea mAb 24." /></a><div class="icnblk_cntnt" id="figlgndpandasF4"><h4 id="pandas.F4"><a href="/books/NBK607260/figure/pandas.F4/?report=objectonly" target="object" rid-ob="figobpandasF4">Figure 4. </a></h4><p class="float-caption no_bottom_margin">Tritiated dopamine release by SKNSH human neuronal cells treated with (A) Sydenham’s chorea mAb 24.3.1, which induced a higher percentage release of 3H-dopamine from SK-N-SH cells than isotype control. SK-N-SH cells were plated at 1 X 106 cells/well. <a href="/books/NBK607260/figure/pandas.F4/?report=objectonly" target="object" rid-ob="figobpandasF4">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpandasF5" co-legend-rid="figlgndpandasF5"><a href="/books/NBK607260/figure/pandas.F5/?report=objectonly" target="object" title="Figure 5. " class="img_link icnblk_img figpopup" rid-figpopup="figpandasF5" rid-ob="figobpandasF5"><img class="small-thumb" src="/books/NBK607260/bin/pandas-Image005.gif" src-large="/books/NBK607260/bin/pandas-Image005.jpg" alt="Figure 5. . Human Sydenham chorea 24." /></a><div class="icnblk_cntnt" id="figlgndpandasF5"><h4 id="pandas.F5"><a href="/books/NBK607260/figure/pandas.F5/?report=objectonly" target="object" rid-ob="figobpandasF5">Figure 5. </a></h4><p class="float-caption no_bottom_margin">Human Sydenham chorea 24.3.1 V gene expressed as a human V gene-mouse IgG1a constant region in Transgenic (Tg) mice targets dopaminergic neurons in the basal ganglia (most likely substantia nigra, based on location). Chimeric Tg24.3.1 VH IgG1a Ab expressed <a href="/books/NBK607260/figure/pandas.F5/?report=objectonly" target="object" rid-ob="figobpandasF5">(more...)</a></p></div></div><p>Pertinent to this discussion, children with PANDAS can present autoreactive anti-neuronal antibodies similar to those observed in SC (<a class="bibr" href="#pandas.REF.chain.2020.564" rid="pandas.REF.chain.2020.564">Chain, et al., 2020</a>; <a class="bibr" href="#pandas.REF.cox.2013.5524" rid="pandas.REF.cox.2013.5524">Cox, et al., 2013</a>; <a class="bibr" href="#pandas.REF.kirvan.2003.914" rid="pandas.REF.kirvan.2003.914">Kirvan, Swedo, Heuser, & Cunningham, 2003</a>; <a class="bibr" href="#pandas.REF.kirvan.2006b.21" rid="pandas.REF.kirvan.2006b.21">Kirvan, Swedo, Kurahara, & Cunningham, 2006b</a>). Additionally, similar autoantibody (AAb)-mediated neuronal signaling mechanisms have been observed as in SC (<a class="bibr" href="#pandas.REF.cox.2013.5524" rid="pandas.REF.cox.2013.5524">Cox, et al., 2013</a>; <a class="bibr" href="#pandas.REF.kirvan.2003.914" rid="pandas.REF.kirvan.2003.914">Kirvan, Swedo, Heuser, & Cunningham, 2003</a>; <a class="bibr" href="#pandas.REF.kirvan.2006b.21" rid="pandas.REF.kirvan.2006b.21">Kirvan, Swedo, Kurahara, & Cunningham, 2006b</a>). Dopamine D2 receptor (D2R) AAbs from PANDAS serum also induce inhibitory D2R signaling similar to SC mAbs and SC serum IgG (<a class="bibr" href="#pandas.REF.cox.2013.5524" rid="pandas.REF.cox.2013.5524">Cox et al., 2013</a>) (<a class="bibr" href="#pandas.REF.cox.2013.5524" rid="pandas.REF.cox.2013.5524">Cox, et al., 2013</a>). In a study of 25 PANDAS cases, 71.4% showed a significant elevation in anti-neuronal mediated signaling via antibody-mediated induction of CaMKII activity in neuronal cells, as detailed in <a class="figpopup" href="/books/NBK607260/figure/pandas.F6/?report=objectonly" target="object" rid-figpopup="figpandasF6" rid-ob="figobpandasF6">Figure 6</a> taken from (<a class="bibr" href="#pandas.REF.chain.2020.564" rid="pandas.REF.chain.2020.564">Chain, et al., 2020</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpandasF6" co-legend-rid="figlgndpandasF6"><a href="/books/NBK607260/figure/pandas.F6/?report=objectonly" target="object" title="Figure 6. " class="img_link icnblk_img figpopup" rid-figpopup="figpandasF6" rid-ob="figobpandasF6"><img class="small-thumb" src="/books/NBK607260/bin/pandas-Image006.gif" src-large="/books/NBK607260/bin/pandas-Image006.jpg" alt="Figure 6. . Comparison of percent serum positive anti-neuronal autoantibody ELISA assays, antibody mediated CaMKII activation, and anti-streptolysin O assay results in PANDAS vs healthy subjects." /></a><div class="icnblk_cntnt" id="figlgndpandasF6"><h4 id="pandas.F6"><a href="/books/NBK607260/figure/pandas.F6/?report=objectonly" target="object" rid-ob="figobpandasF6">Figure 6. </a></h4><p class="float-caption no_bottom_margin">Comparison of percent serum positive anti-neuronal autoantibody ELISA assays, antibody mediated CaMKII activation, and anti-streptolysin O assay results in PANDAS vs healthy subjects. Taken from (Chain, et al., 2020). </p></div></div><p>Antibody-mediated CaMKII neuronal signaling was initially observed to be triggered by SC serum AAbs and the mAb 24.3.1 (<a class="bibr" href="#pandas.REF.kirvan.2003.914" rid="pandas.REF.kirvan.2003.914">Kirvan, Swedo, Heuser, & Cunningham, 2003</a>; <a class="bibr" href="#pandas.REF.kirvan.2006b.21" rid="pandas.REF.kirvan.2006b.21">Kirvan, Swedo, Kurahara, & Cunningham, 2006b</a>). CaMKII is instrumental in synaptic plasticity, dendritic spine morphology, neurotransmitter release, and intracellular signaling (<a class="bibr" href="#pandas.REF.hell.2014.249" rid="pandas.REF.hell.2014.249">Hell, 2014</a>; <a class="bibr" href="#pandas.REF.lisman.1994.406" rid="pandas.REF.lisman.1994.406">Lisman J. , 1994</a>; <a class="bibr" href="#pandas.REF.lisman.2002.175" rid="pandas.REF.lisman.2002.175">Lisman, Schulman, & Cline, 2002</a>; <a class="bibr" href="#pandas.REF.lisman.2012.169" rid="pandas.REF.lisman.2012.169">Lisman, Yasuda, & Raghavachari, 2012</a>; <a class="bibr" href="#pandas.REF.stein.2014.193" rid="pandas.REF.stein.2014.193">Stein, Donaldson, & Hell, 2014</a>). Aberrant CaMKII signaling may disrupt these pathways and cause functional deficits and potential complications in both SC and PANDAS. It is important to note that 71.4% of the PANDAS group also exhibited a significant abnormal elevation of autoantibody titers against the dopamine receptor 1(D1R) (<a class="figpopup" href="/books/NBK607260/figure/pandas.F6/?report=objectonly" target="object" rid-figpopup="figpandasF6" rid-ob="figobpandasF6">Figure 6</a>; <a class="bibr" href="#pandas.REF.chain.2020.564" rid="pandas.REF.chain.2020.564">Chain, et al., 2020</a>)<b>.</b> In a recent study in revision, D1R AAbs were found to be significantly elevated with high specificity and sensitivity across three PANDAS cohorts (Menendez, 2024). Furthermore, recent unpublished data submitted and in revision (Menendez, 2024) shows when cell lines expressing the human D1R were treated with the first PANDAS derived human mAbs or PANDAS serum AAbs, the D1R-reactive AAbs increased D1R signaling and the receptors’ sensitivity to dopamine. Both D1R and D2R AAbs were also found in PANDAS CSF (<a class="bibr" href="#pandas.REF.chain.2020.564" rid="pandas.REF.chain.2020.564">Chain, et al., 2020</a>).</p><p>Singer and colleagues detected positive serum reactivity via IHC membrane staining in striatal brain tissue, as well as with GFAP+ glial cells and MAP2 positive neuronal cells in both PANDAS and Tourette syndrome patients (<a class="bibr" href="#pandas.REF.morris.2009.45" rid="pandas.REF.morris.2009.45">Morris, Pardo-Villamizar, Gause, & Singer, 2009</a>). However, due to the small number of groups analyzed and potentially limited power and assay sensitivity, they did not identify significant differences in reactivity when compared to controls. Furthermore, they found no differences in ELISA optical densities for anti-tubulin or anti-D2R antibodies (<a class="bibr" href="#pandas.REF.morrisberry.2013.106" rid="pandas.REF.morrisberry.2013.106">Morris-Berry, et al., 2013</a>). It is important to note that IHC assays are not as sensitive as signaling or ELISA assays. In their studies, there appeared to be a trend towards increased anti-tubulin reactivity in Tourette syndrome patients with exacerbated symptoms, as well as in PANDAS patients with and without exacerbated symptoms. Titrating differences might have yielded greater sensitivity in their findings. Recent studies on PANDAS cohorts do not consistently show significant elevations in D2R antibodies, but lean more towards associations with D1R autoantibodies in our new evidence, which shows significant D1R elevations in PANDAS and significant D2R elevations in Sydenham chorea (<a class="bibr" href="#pandas.REF.menendez.2024" rid="pandas.REF.menendez.2024">Menendez, et al., 2024</a>).</p><p>A more recent study by <a class="bibr" href="#pandas.REF.singer.2015.e0120499" rid="pandas.REF.singer.2015.e0120499">Singer and colleagues (2015)</a> demonstrated that SC antineuronal antibodies were able to identify children with PANDAS (albeit labeled as “chronic recurrent episodic acute exacerbations of tics and OCD following a streptococcal infection”) (<a class="bibr" href="#pandas.REF.singer.2015.e0120499" rid="pandas.REF.singer.2015.e0120499">Singer, et al., 2015</a>). Shimasaki, et al. compared pre- and post-treatment antibody titers for 56 patients who met PANS/PANDAS criteria and found that the group of anti-neuronal AAbs correlated well with symptom improvement, with an overall accuracy of 90%, a sensitivity of 88%, specificity of 92%, and an Area Under the Curve value of 95.7% (<a class="bibr" href="#pandas.REF.shimasaki.2020.577138" rid="pandas.REF.shimasaki.2020.577138">Shimasaki, et al., 2020</a>).</p><p>In a study involving a heterogeneous group of youth and young adults with tics and OCD, all of whom had confirmed streptococcal infections or positive streptococcal test results, it was found that participants with tics and/or chronic OCD exhibited significantly elevated anti-D1R IgG AAbs titers, as compared to healthy controls (<a class="bibr" href="#pandas.REF.cox.2015.76" rid="pandas.REF.cox.2015.76">Cox, et al., 2015</a>). The same study found a significant association between the presence of OCD and/or tics and positive streptococcal infection status (p = 0.0087), which suggests a link between streptococcal infections and the occurrence of these conditions. Notably, individuals who tested positive for streptococcal infections were more likely to exhibit both OCD and tics (51%), as compared to those who tested negative for streptococcal infection (30%). However, no significant association was observed when considering tics or OCD in isolation without infection. In this study, individuals with tics and/or OCD (n=261) demonstrated strong evidence of elevated serum IgG antibodies against human D1R (p<0.0001), lysoganglioside (p=0.0001), and heightened activation of CaMKII activity (p<0.0001) when compared to a control group of healthy individuals (n=16). Moreover, among the cohort with tics and/or OCD, children exhibited significantly increased activation of CaMKII activity, as compared to those with either tics or OCD alone (p<0.033 for each) (<a class="bibr" href="#pandas.REF.cox.2015.76" rid="pandas.REF.cox.2015.76">Cox, et al., 2015</a>).</p><p>Given the broad variety of signs and symptoms present in PANDAS, it is likely that future research investigations will identify additional immune mechanisms and categories of autoantibodies. Such studies are welcomed, as they’re likely to yield important information about the neurotransmitters and neural support structures involved in OCD, eating disorders, depression, anxiety and other disorders. Recent research from Yale University has shown that antibodies from PANDAS patients specifically target cholinergic interneurons and alter their function (<a class="bibr" href="#pandas.REF.frick.2018.304" rid="pandas.REF.frick.2018.304">Frick, et al., 2018</a>; <a class="bibr" href="#pandas.REF.xu.2021.48" rid="pandas.REF.xu.2021.48">Xu, et al., 2021</a>). Improvements in PANDAS symptoms following intravenous immunoglobulin (IVIG) treatment were found to be associated with a decrease in anti-cholinergic antibody titers and a decline in the bioactivity of convalescent sera (<a class="bibr" href="#pandas.REF.xu.2021.48" rid="pandas.REF.xu.2021.48">Xu, et al., 2021</a>). This correlation has also been observed in humans, where reductions in CaMKII activity and autoantibodies against dopamine receptors were linked to symptom improvement (<a class="bibr" href="#pandas.REF.chain.2020.564" rid="pandas.REF.chain.2020.564">Chain, et al., 2020</a>; <a class="bibr" href="#pandas.REF.shimasaki.2020.577138" rid="pandas.REF.shimasaki.2020.577138">Shimasaki, et al., 2020</a>). These findings suggest a potential integration of these factors, especially when considering the centralization of dopamine receptors in the basal ganglia and the notable involvement of cholinergic neurons that may contribute to the manifestation of symptoms such as tics (<a class="bibr" href="#pandas.REF.bernstein.2010.333" rid="pandas.REF.bernstein.2010.333">Bernstein, Victor, Pipal, & Williams, 2010</a>; <a class="bibr" href="#pandas.REF.giedd.2000.281" rid="pandas.REF.giedd.2000.281">Giedd, Rapoport, Garvey, Perlmutter, & Swedo, 2000</a>). To further support the autoimmune nature of SC and PANDAS, a position statement about autoimmune psychoses was addressed in <i>The Lancet</i> (<a class="bibr" href="#pandas.REF.pollak.2020.93" rid="pandas.REF.pollak.2020.93">Pollak, et al., 2020</a>) and defines dopamine receptor autoantibodies as biomarkers associated with SC and PANDAS (<a class="bibr" href="#pandas.REF.cox.2013.5524" rid="pandas.REF.cox.2013.5524">Cox, et al., 2013</a>; <a class="bibr" href="#pandas.REF.cunningham.2016.90" rid="pandas.REF.cunningham.2016.90">Cunningham & Cox, 2016</a>), which are considered in that report to be autoimmune psychoses.</p><p>The diagram in <a class="figpopup" href="/books/NBK607260/figure/pandas.F7/?report=objectonly" target="object" rid-figpopup="figpandasF7" rid-ob="figobpandasF7">Figure 7</a> provides a possible explanation for the interaction of the anti-cholinergic, anti-dopaminergic, and CaMKII signaling antibodies that have been demonstrated in SC and PANDAS. The diagram focuses on the <i>S. pyogenes</i> associated cross-reactive autoantibodies and their targeting the dopamine D1R and D2R receptors. Evidence from Ben-Pazi, et al. (<a class="bibr" href="#pandas.REF.benpazi.2013.e73516" rid="pandas.REF.benpazi.2013.e73516">Ben-Pazi, Stoner, & Cunningham, 2013</a>) and Menendez, et al. (Menendez, 2024) explains how the combination of autoantibodies against the receptors may play a role in symptomatic behaviors of involuntary movements in chorea versus neuropsychiatric symptoms involved in OCD and tics.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpandasF7" co-legend-rid="figlgndpandasF7"><a href="/books/NBK607260/figure/pandas.F7/?report=objectonly" target="object" title="Figure 7. " class="img_link icnblk_img figpopup" rid-figpopup="figpandasF7" rid-ob="figobpandasF7"><img class="small-thumb" src="/books/NBK607260/bin/pandas-Image007.gif" src-large="/books/NBK607260/bin/pandas-Image007.jpg" alt="Figure 7. . Autoantibody-mediated signaling in PANDAS, a basal ganglia encephalitis: Mechanisms for autoimmune movement and behavioral disorders." /></a><div class="icnblk_cntnt" id="figlgndpandasF7"><h4 id="pandas.F7"><a href="/books/NBK607260/figure/pandas.F7/?report=objectonly" target="object" rid-ob="figobpandasF7">Figure 7. </a></h4><p class="float-caption no_bottom_margin">Autoantibody-mediated signaling in PANDAS, a basal ganglia encephalitis: Mechanisms for autoimmune movement and behavioral disorders. In Sydenham’s chorea and PANDAS, neurons in the basal ganglia are attacked by autoantibodies against the group <a href="/books/NBK607260/figure/pandas.F7/?report=objectonly" target="object" rid-ob="figobpandasF7">(more...)</a></p></div></div><p>This hypothesis was supported in the study of SC by Ben-Pazi, where a ratio of D2R/D1R antibody titers gave rise to a ratio which correlated significantly and directly with symptoms (<a class="bibr" href="#pandas.REF.benpazi.2013.e73516" rid="pandas.REF.benpazi.2013.e73516">Ben-Pazi, Stoner, & Cunningham, 2013</a>). This ratio is likely to dictate the symptoms in either SC or PANDAS. There may also be a biomarker of disease, which is the GlcNAc-specific IgG2 autoantibodies (<a class="bibr" href="#pandas.REF.kirvan.2023.919700" rid="pandas.REF.kirvan.2023.919700">Kirvan, et al., 2023</a>) that may arise only in ARF, RHD, SC, and PANDAS but not in uncomplicated streptococcal infections. Studies in PANDAS for this biomarker will be important in the future to better understand disease risk and development. This hypothesis is supported in Ben-Pazi's study of SC, where a significant and direct correlation was observed between symptoms and the ratio of D2R/D1R antibody titers (<a class="bibr" href="#pandas.REF.benpazi.2013.e73516" rid="pandas.REF.benpazi.2013.e73516">Ben-Pazi, Stoner, & Cunningham, 2013</a>). This ratio is likely to play a crucial role in determining symptoms in both SC and PANDAS. Additionally, a GlcNAc-specific IgG2 biomarker of disease, represented by IgG2 GlcNAc-specific autoantibodies, has been identified for SC and ARF/RHD (<a class="bibr" href="#pandas.REF.kirvan.2023.919700" rid="pandas.REF.kirvan.2023.919700">Kirvan, et al., 2023</a>). This biomarker appears to be unique to ARF, RHD, and SC, CF, and SC sera, distinguishing them from uncomplicated streptococcal infections. Future studies on PANDAS that focus on this biomarker will be essential for a more comprehensive understanding of disease risk and development.</p><p>Animal models of abnormal movements and repetitive behaviors (akin to OCD rituals) provide opportunities for <i>in vivo</i> explorations of the role of antineuronal antibodies and the effect of repeated <i>S. pyogenes</i> infections. Serologic studies in children with Tourette syndrome (TS) have identified anti-neuronal antibodies (<a class="bibr" href="#pandas.REF.kiessling.1993.39" rid="pandas.REF.kiessling.1993.39">Kiessling, Marcotte, & Culpepper, 1993</a>; <a class="bibr" href="#pandas.REF.morshed.2001.566" rid="pandas.REF.morshed.2001.566">Morshed, et al., 2001</a>), and their functional role was illuminated by evidence that involuntary movements akin to TS could be triggered in rats through the administration of TS sera or IgG into the striatum (<a class="bibr" href="#pandas.REF.hallett.2000.195" rid="pandas.REF.hallett.2000.195">Hallett, Harling-Berg, Knopf, Stopa, & Kiessling, 2000</a>; <a class="bibr" href="#pandas.REF.taylor.2002.657" rid="pandas.REF.taylor.2002.657">Taylor, et al., 2002</a>).</p><p>In further studies, immunization of mice with streptococcal antigens in Freund’s complete adjuvant led to behavioral alterations and compulsions, as well as a subset of mice with antibody deposits in several brain regions, including deep cerebellar nuclei (DCN), globus pallidus, and the thalamus (<a class="bibr" href="#pandas.REF.hoffman.2004.1780" rid="pandas.REF.hoffman.2004.1780">Hoffman, Hornig, Yaddanapudi, Jabado, & Lipkin, 2004</a>). <i>S. pyogenes</i>-immunized mice with increased deposits of IgG in the deep cerebellar nuclei exhibited increased rearing behavior, as compared to controls (<a class="bibr" href="#pandas.REF.hoffman.2004.1780" rid="pandas.REF.hoffman.2004.1780">Hoffman, Hornig, Yaddanapudi, Jabado, & Lipkin, 2004</a>).</p><p>Rat models reveal similar findings: exposure to <i>S. pyogenes</i> antigens induce motor and behavioral changes linked to central dopaminergic pathway dysfunction and antibody deposition in the striatum, thalamus, and frontal cortex (<a class="bibr" href="#pandas.REF.brimberg.2012.2076" rid="pandas.REF.brimberg.2012.2076">Brimberg, et al., 2012</a>; <a class="bibr" href="#pandas.REF.lotan.2014b.e101257" rid="pandas.REF.lotan.2014b.e101257">Lotan, Cunningham, & Joel, 2014b</a>). IgG deposits in the thalamus paralleled behavioral deficits and motor deficits. Continuous treatment with the antibiotic ampicillin mitigated the emergence of these <i>S. pyogenes</i>-induced alterations, reduced IgG deposition in the thalamus, and tended to normalize the elevated levels of D1 and D2 dopamine receptors and tyrosine hydroxylase in the striatum (<a class="bibr" href="#pandas.REF.lotan.2014b.e101257" rid="pandas.REF.lotan.2014b.e101257">Lotan, Cunningham, & Joel, 2014b</a>). In the Lewis rat model, AAbs reacted with the D1 and D2 receptors, and behavioral and motor symptoms were alleviated by the D2R antagonist, haloperidol, and selective serotonin reuptake inhibitor paroxetine (<a class="bibr" href="#pandas.REF.brimberg.2012.2076" rid="pandas.REF.brimberg.2012.2076">Brimberg, et al., 2012</a>).</p><p>Importantly, passive transfer of anti-streptococcal antibodies from <i>S. pyogenes</i> immunized Lewis rats or mice led to behavior changes in the recipient rodents that were identical to those seen in the donor mice, and they demonstrated autoantibody deposits in the striatum and thalamus (<a class="bibr" href="#pandas.REF.lotan.2014b.e101257" rid="pandas.REF.lotan.2014b.e101257">Lotan, Cunningham, & Joel, 2014b</a>; <a class="bibr" href="#pandas.REF.yaddanapudi.2010.712" rid="pandas.REF.yaddanapudi.2010.712">Yaddanapudi, et al., 2010</a>). These findings fulfill the last of Witebsky’s postulates that define a disorder as “autoimmune” (<a class="bibr" href="#pandas.REF.rose.1993.426" rid="pandas.REF.rose.1993.426">Rose & Bona, 1993</a>) and provide support for an etiologic role of <i>S. pyogenes</i> antigen exposure and development of antineuronal antibodies in the pathogenesis of PANDAS and SC.</p><p>Dileepan and colleagues used a mouse model to study the pathologic role of <i>S. pyogenes</i> bacteria in PANDAS (<a class="bibr" href="#pandas.REF.dileepan.2011.e1002252" rid="pandas.REF.dileepan.2011.e1002252">Dileepan, et al., 2011</a>; <a class="bibr" href="#pandas.REF.dileepan.2016.303" rid="pandas.REF.dileepan.2016.303">Dileepan, et al., 2016</a>). They found that repeated intranasal <i>S. pyogenes</i> infections produced migration of streptococcal-specific Th17 cells from the nasal-associated lymphoid tissue (NALT; the equivalent of human adenoids) into the CNS via olfactory sensory neurons. This finding was further corroborated by Wayne, et al. (<a class="bibr" href="#pandas.REF.wayne.2023.2023.03.10.532135" rid="pandas.REF.wayne.2023.2023.03.10.532135">Wayne, et al., 2023</a>),whose study using human samples confirmed and replicated the findings by demonstrating a crucial role for Th17-derived cytokines in PANDAS. In addition to Th17 trafficking, the mouse model demonstrated inflammation-mediated breakdown of the blood-brain barrier (BBB), microglial activation, serum IgG deposition and loss of excitatory synaptic proteins (<a class="bibr" href="#pandas.REF.dileepan.2016.303" rid="pandas.REF.dileepan.2016.303">Dileepan, et al., 2016</a>; <a class="bibr" href="#pandas.REF.platt.2020.6708" rid="pandas.REF.platt.2020.6708">Platt, et al., 2020</a>). Disruption of the blood-brain barrier (BBB) would provide a means for peripheral autoantibodies, as well as cytokines, to enter the CNS (<a class="bibr" href="#pandas.REF.platt.2017.442" rid="pandas.REF.platt.2017.442">Platt, Agalliu, & Cutforth, 2017</a>). One particularly interesting aspect of this line of investigation was the finding that multiple <i>S. pyogenes</i> infections are required to provoke neuroinflammation—if multiple infections also are required for humans to demonstrate post-<i>S. pyogenes</i> sequelae, it could provide an explanation for the frequent, but puzzling scenario where two children get infected with the same M type of <i>S. pyogenes</i>, but only one has post-<i>S. pyogenes</i> sequelae. This has been shown in rheumatic fever as well where multiple immunizations are required to invoke the symptoms of rheumatic heart disease in the Lewis rat model; repeated exposure to group A streptococcal M protein exacerbates cardiac damage in the rat model of rheumatic heart disease (<a class="bibr" href="#pandas.REF.gorton.2016.563" rid="pandas.REF.gorton.2016.563">Gorton, et al., 2016</a>).</p></div></div><div id="pandas.Underlying_Potential_Mechanisms_o"><h2 id="_pandas_Underlying_Potential_Mechanisms_o_">Underlying Potential Mechanisms of Disease Pathogenesis in the Streptococcal Sequelae: Autoimmunity and Genetics in Rheumatic Fever and PANDAS and Systemic Autoimmune Diseases such as Systemic Lupus Erythematosus</h2><div id="pandas.Autoimmune_diseases_and_ARF"><h3>Autoimmune diseases and ARF</h3><p>Antinuclear autoantibodies (ANA), which are very common in systemic lupus erythematosus (SLE) are positive in some cases of PANDAS (<a class="bibr" href="#pandas.REF.frankovich.2017.574" rid="pandas.REF.frankovich.2017.574">Frankovich, et al., 2017</a>). In addition, anti-idiotypic antibodies, developed against autoantibodies in ARF, identified closely connected serum antibodies from SLE and Sjogren’s syndrome (SS) (<a class="bibr" href="#pandas.REF.mccormack.1993.915" rid="pandas.REF.mccormack.1993.915">McCormack, Crossley, Ayoub, Harley, & Cunningham, 1993</a>) with streptococcal sequelae, which suggests that PANDAS and all streptococcal sequelae may be related to similar mechanisms found in systemic autoimmune diseases, such as SLE and SS. More recent work has identified another connection between SLE and rheumatic heart disease (RHD) in that estrogen drives CD8+ T cells to upregulate perforin and granzyme in rheumatic heart valves (<a class="bibr" href="#pandas.REF.passos.2022.531" rid="pandas.REF.passos.2022.531">Passos, et al., 2022</a>) where women are more at risk and have more valve disease. Further, complement Factor C4 deficiencies have been identified as a genetic susceptibility trait in SLE (<a class="bibr" href="#pandas.REF.macedo.2016.55" rid="pandas.REF.macedo.2016.55">Macedo & Isaac, 2016</a>), as well as in PANS/PANDAS (<a class="bibr" href="#pandas.REF.kalinowski.2023.315" rid="pandas.REF.kalinowski.2023.315">Kalinowski, et al., 2023</a>). Autoimmune genes that may lead to problems in RHD, SLE, and SS may contribute to the overall similarities in these autoimmune diseases when mostly women are afflicted. This is different in PANDAS, where boys are 3:1 with girls being less affected. See a more detailed discussion of these points below in the Genetic Susceptibility section.</p><p>In the rheumatic diseases, namely ARF and RHD, repeated streptococcal infections/tonsillitis were related to alterations in the T follicular cell compartment where the germinal centers were smaller and gave rise to reduced antibody production against group A streptococcal infection (<a class="bibr" href="#pandas.REF.dan.2019.eaau3776" rid="pandas.REF.dan.2019.eaau3776">Dan, et al., 2019</a>). Such defects in the immune system of children may play a specific and detrimental role in those in particular who carry the susceptibility genes for rheumatic diseases. It was noted that those with the alteration in T follicular helper cells where reduced antibody production had effects on outcomes in infection. These children also had HLA risk alleles identified in the same study (<a class="bibr" href="#pandas.REF.dan.2019.eaau3776" rid="pandas.REF.dan.2019.eaau3776">Dan, et al., 2019</a>).</p></div><div id="pandas.Genetic_susceptibility"><h3>Genetic susceptibility</h3><p>Genetic susceptibility is an important risk factor in ARF (<a class="bibr" href="#pandas.REF.muhamed.2020.145" rid="pandas.REF.muhamed.2020.145">Muhamed, Parks, & Sliwa, 2020</a>). Susceptibility to ARF and RHD may result from variations in host genes, which may be potential risk factors for disease. Thus, identifying genetic associations may be important in understanding the immune responses that can be misdirected toward heart, joints, or the brain, and that lead to carditis, arthritis, or Sydenham’s chorea in ARF, or neuropsychiatric disease in PANDAS. In some studies of ARF, familial associations were found to be inherited with limited penetrance and concordance among dizygotic twins, which suggests an inherited susceptibility, but not classical Mendelian genetics (<a class="bibr" href="#pandas.REF.bryant.2009.742" rid="pandas.REF.bryant.2009.742">Bryant, Robins-Browne, Carapetis, & Curtis, 2009</a>). Genetic associations and polymorphisms have been found in several immune related genes as described herein. C4 deficiencies are a well-known risk factor in systemic lupus erythematosus or in some forms of arthritis (<a class="bibr" href="#pandas.REF.yang.2004.98" rid="pandas.REF.yang.2004.98">Yang, et al., 2004</a>), and now C4 deficiency with reduced copy number has been found also in pediatric acute neuropsychiatric syndrome or PANS (<a class="bibr" href="#pandas.REF.kalinowski.2023.315" rid="pandas.REF.kalinowski.2023.315">Kalinowski, et al., 2023</a>) and was mainly associated with arthritis. ARF and RHD are associated with SLE in several ways. First, anti-idiotypic antibody reagents prepared against purified cardiac myosin AAbs from RHD were shown to detect specific RHD autoantibodies (<a class="bibr" href="#pandas.REF.mccormack.1993.915" rid="pandas.REF.mccormack.1993.915">McCormack, Crossley, Ayoub, Harley, & Cunningham, 1993</a>) not only in RHD and ARF, but also very strongly in SLE and Sjogren’s syndrome. Further, the My1 antibody idiotypic biomarker of RHD anti-cardiac myosin autoantibodies (<a class="bibr" href="#pandas.REF.mccormack.1993.915" rid="pandas.REF.mccormack.1993.915">McCormack, Crossley, Ayoub, Harley, & Cunningham, 1993</a>) may be related to the immunoglobulin VH gene(s) found to be genetically associated with RHD, where a common immunoglobulin heavy chain allele was found associated with rheumatic heart disease risk in Oceania (<a class="bibr" href="#pandas.REF.parks.2017.14946" rid="pandas.REF.parks.2017.14946">Parks, et al., 2017</a>) and in South Africa and Europe (<a class="bibr" href="#pandas.REF.machipisa.2021.1000" rid="pandas.REF.machipisa.2021.1000">Machipisa, et al., 2021</a>). These combined findings lead to speculation that there might be immunoglobulin VH germ line genes that are specifically associated with the idiotypic structure of the VH region of idiotype-specific anti-cardiac myosin cross-reactive antibodies. Autoantibodies in mice when immunized with streptococcal membranes gave rise to anti-DNA autoantibodies that again connect group A streptococcal immune responses with autoimmunity in SLE (<a class="bibr" href="#pandas.REF.cunningham.1986.998" rid="pandas.REF.cunningham.1986.998">Cunningham & Swerlick, 1986</a>). RHD does not have positive antinuclear autoantibodies, but about 50 percent of cases with PANDAS, a neuropsychiatric streptococcal sequelae, have elevated antinuclear autoantibodies (<a class="bibr" href="#pandas.REF.chang.2015.3" rid="pandas.REF.chang.2015.3">Chang, et al., 2015</a>). Second, further associations of ARF/RHD with SLE include the fact that the largest amount of valve disease is found in women and is associated not only with CD4+ T cells but also with cytotoxic CD8+ T cells that are sensitive to estradiol treatment leading to elevations of cytotoxic perforin and granzyme in the presence of antigen (<a class="bibr" href="#pandas.REF.passos.2022.531" rid="pandas.REF.passos.2022.531">Passos, et al., 2022</a>). Thus, estrogen would lead to increased valvular damage in women and was reported to upregulate the cytotoxicity, as well as HLA class I, on the CD8+ T cells studied from RHD (<a class="bibr" href="#pandas.REF.passos.2022.531" rid="pandas.REF.passos.2022.531">Passos, et al., 2022</a>).</p><p>In ARF and RHD, susceptibility to disease may be linked to HLA predisposition, as is the case for many autoimmune-related diseases. HLA class II human leukocyte antigen (HLA-ll) predisposition may occur with different HLA alleles reportedly associated with RHD susceptibility in different ethnic populations (<a class="bibr" href="#pandas.REF.guilherme.1991.1995" rid="pandas.REF.guilherme.1991.1995">Guilherme, Weidebach, Kiss, Snitcowsky, & Kalil, 1991</a>; <a class="bibr" href="#pandas.REF.taneja.1989.335" rid="pandas.REF.taneja.1989.335">Taneja, et al., 1989</a>; <a class="bibr" href="#pandas.REF.ozkan.1993.1974" rid="pandas.REF.ozkan.1993.1974">Ozkan, et al., 1993</a>; <a class="bibr" href="#pandas.REF.weidebach.1994.253" rid="pandas.REF.weidebach.1994.253">Weidebach, et al., 1994</a>; <a class="bibr" href="#pandas.REF.visentainer.2000.1518" rid="pandas.REF.visentainer.2000.1518">Visentainer, et al., 2000</a>; <a class="bibr" href="#pandas.REF.stanevicha.2003.r340" rid="pandas.REF.stanevicha.2003.r340">Stanevicha, et al., 2003</a>). In rheumatic heart disease, the DR-7 haplotype has been associated with mitral valve disease in a large Latvian population (>1200 children), along with several other haplotypes that conferred risk or protection (<a class="bibr" href="#pandas.REF.stanevicha.2003.r340" rid="pandas.REF.stanevicha.2003.r340">Stanevicha, et al., 2003</a>), and HLA haplotype DR-7 has been linked to rheumatic heart disease in the Brazilian population (<a class="bibr" href="#pandas.REF.guilherme.1991.1995" rid="pandas.REF.guilherme.1991.1995">Guilherme, Weidebach, Kiss, Snitcowsky, & Kalil, 1991</a>; <a class="bibr" href="#pandas.REF.guilherme.2006.31" rid="pandas.REF.guilherme.2006.31">Guilherme, Kalil, & Cunningham, 2006</a>) as well as in the Egyptian and Turkish populations (<a class="bibr" href="#pandas.REF.guilherme.2011.13" rid="pandas.REF.guilherme.2011.13">Guilherme, Köhler, Postol, & Kalil, 2011</a>). Other genes such as polymorphisms in cytokine genes, which have been associated with rheumatic fever and rheumatic heart disease, and a more detailed discussion of HLA haplotypes has been performed by Guilherme et al. (<a class="bibr" href="#pandas.REF.guilherme.2011.13" rid="pandas.REF.guilherme.2011.13">Guilherme, Köhler, Postol, & Kalil, 2011</a>). Genes that were associated with rheumatic fever included a TLR 2 polymorphism. Berdeli, et al. reported that the common TLR-2 Arg to Gln polymorphism at position 753 was significantly (p<0.0001) associated with acute rheumatic fever in a Caucasian Turkish population, as compared to controls. It is interesting that our recent study in humans reported human cardiac myosin or its fragments to be a TLR2 ligand and bind to human TLR 2, which stimulated monocytes to produce proinflammatory cytokines (<a class="bibr" href="#pandas.REF.zhang.2009.27" rid="pandas.REF.zhang.2009.27">Zhang, Cox, Alvarez, & Cunningham, 2009</a>).</p><p>Recent findings suggest that the class III region of the HLA complex in a South Asian dataset and replicated in a European dataset may be a hotspot for risk susceptibility in RHD and offer new insight into pathogenesis (<a class="bibr" href="#pandas.REF.auckland.2020.9004" rid="pandas.REF.auckland.2020.9004">Auckland, et al., 2020</a>). The class III region also harbors complement genes that may be important for reasons described herein. Additional genes linked to rheumatic fever include the mannose-binding lectin gene O allele, which was associated with aortic regurgitation in rheumatic heart disease. The mannose binding lectin allele encodes for a lower production of the protein and is associated with increased risk of rheumatic fever and rheumatic heart disease (<a class="bibr" href="#pandas.REF.guilherme.2011.13" rid="pandas.REF.guilherme.2011.13">Guilherme, Köhler, Postol, & Kalil, 2011</a>; <a class="bibr" href="#pandas.REF.ramasawmy.2008.932" rid="pandas.REF.ramasawmy.2008.932">Ramasawmy, et al., 2008</a>). Mannose-binding lectin is important in clearance of bacteria and is associated with the complement system (<a class="bibr" href="#pandas.REF.guilherme.2011.13" rid="pandas.REF.guilherme.2011.13">Guilherme, Köhler, Postol, & Kalil, 2011</a>). The FcR-gamma-IIA receptor gene may express a polymorphism, which causes differences in binding of IgG2 in humans. Turkish children with a high risk of developing rheumatic fever possessed the <i>131R/R</i> genotype of FcR-gamma-IIA, and the <i>131H/R</i> allele of the FcR-gamma-IIA was associated with an intermediate risk (<a class="bibr" href="#pandas.REF.berdeli.2004.925" rid="pandas.REF.berdeli.2004.925">Berdeli, Celik, Ozyürek, & Aydin, 2004</a>). Failure to clear immune complexes from the blood may potentially lead to the continued development of high-affinity antibodies (<a class="bibr" href="#pandas.REF.zhang.2013.457" rid="pandas.REF.zhang.2013.457">Zhang, et al., 2013</a>) that would attack the heart, brain, or other tissue sites in rheumatic fever. HLA B5 has been associated with immune complexes in acute rheumatic fever (<a class="bibr" href="#pandas.REF.yoshinoya.1980.136" rid="pandas.REF.yoshinoya.1980.136">Yoshinoya & Pope, 1980</a>). These genetic associations are important to note as they are involved in inflammatory and immune responses against the streptococcus, and potentially predispose those who possess them to rheumatic heart disease. Gene variations have been reported in RHD in the C4 complement factor (<a class="bibr" href="#pandas.REF.chung.2020.12" rid="pandas.REF.chung.2020.12">Chung, et al., 2020</a>), in TGF-beta1 (<a class="bibr" href="#pandas.REF.karthikeyan.2020.2091" rid="pandas.REF.karthikeyan.2020.2091">Karthikeyan, Fung, & Foo, 2020</a>), in mannose binding protein, and in FcR loci and these genetic variations may be related to pathogenesis (<a class="bibr" href="#pandas.REF.guilherme.2011.13" rid="pandas.REF.guilherme.2011.13">Guilherme, Köhler, Postol, & Kalil, 2011</a>; <a class="bibr" href="#pandas.REF.ramasawmy.2008.932" rid="pandas.REF.ramasawmy.2008.932">Ramasawmy, et al., 2008</a>).</p><p>Further, the Moreland laboratory used an integrative statistical approach with feature selection and principal component analysis to demonstrate a linked elevated IgG3–C4 response in ARF cases with high C-reactive protein responses that were not found in controls (<a class="bibr" href="#pandas.REF.chung.2020.12" rid="pandas.REF.chung.2020.12">Chung, et al., 2020</a>). IgG3 and C4 were found together elevated above clinical reference ranges, which suggests that they may be potential biomarkers of early stages of ARF and inflammation and identify children at risk. IgG3-C4 susceptibility genes may play a role in development and risk of RHD and ARF. A recent review (<a class="bibr" href="#pandas.REF.abdallah.2021.611036" rid="pandas.REF.abdallah.2021.611036">Abdallah & Abu-Madi, 2021</a>) summarizes the pathogenesis with a summary of the HLA class II and III alleles, and indicates the various results of the three GWAS studies. GWAS 1 defined the IGHV4-61 risk allele (<a class="bibr" href="#pandas.REF.parks.2017.14946" rid="pandas.REF.parks.2017.14946">Parks, et al., 2017</a>). The HLA risk haplotypes included DQA1*0101_DQB1*0503 and DQA1*0103_DQB1*0601and protective haplotype DQA1*0301-DQB1*0402 which provided support for the molecular mimicry hypothesis (<a class="bibr" href="#pandas.REF.abdallah.2021.611036" rid="pandas.REF.abdallah.2021.611036">Abdallah & Abu-Madi, 2021</a>).</p><p>Although host susceptibility may be a result of host genetic predisposition, the environmental influence exerted by <i>S. pyogenes</i> on host-streptococcal interactions is extremely important in the development of rheumatic fever and RHD, as well as PANDAS. While the role of specific streptococcal strain variations in acute rheumatic fever may not be well characterized in epidemics of rheumatic fever, there have been reports of a relationship between rheumatic-fever–associated strains that were isolated from the great acute rheumatic fever epidemics of the World War II era where the <i>S. pyogenes</i> were rich in M protein, heavily encapsulated by hyaluronic acid, and highly virulent in mice (<a class="bibr" href="#pandas.REF.stollerman.2001.806" rid="pandas.REF.stollerman.2001.806">Stollerman, 2001</a>). These highly mucoid strains primarily infected the throat rather than the skin and were also seen with the rheumatic fever outbreak in Utah in the United States (<a class="bibr" href="#pandas.REF.veasy.2004.e168" rid="pandas.REF.veasy.2004.e168">Veasy, et al., 2004</a>). In the past, certain M protein serotypes were associated with rheumatic fever outbreaks, such as the well-known M5 protein serotype (<a class="bibr" href="#pandas.REF.bisno.1995" rid="pandas.REF.bisno.1995">Bisno, 1995</a>; <a class="bibr" href="#pandas.REF.bisno.1970.561" rid="pandas.REF.bisno.1970.561">Bisno, Pearce, Wall, Moody, & Stollerman, 1970</a>). <i>S. pyogenes</i> strains isolated in more tropical climates do not have the characteristics of these earlier strains isolated in North America. The epidemiology suggests a greater diversity of <i>S. pyogenes</i> strains, and skin-associated strains may dominate in ARF in the more tropical regions (<a class="bibr" href="#pandas.REF.bryant.2009.742" rid="pandas.REF.bryant.2009.742">Bryant, Robins-Browne, Carapetis, & Curtis, 2009</a>).</p></div><div id="pandas.Immunomodulatory_Treatment_Provid"><h3>Immunomodulatory Treatment Provides Evidence of Immune Dysfunction in PANDAS</h3><p>Immune dysfunction in PANDAS appears to occur at multiple levels: local (targeted) dysfunction secondary to antineuronal antibodies; regional abnormalities related to inflammation within neuronal tissues or vasculature of the basal ganglia; and systemic abnormalities of cytokine and chemokine production, which can result in the disruption of the blood-brain barrier and CNS functions (<a class="bibr" href="#pandas.REF.cutforth.2016.63" rid="pandas.REF.cutforth.2016.63">Cutforth, Mc DeMille, Agalliu, & Agalliu, 2016</a>; <a class="bibr" href="#pandas.REF.williams.2015.144" rid="pandas.REF.williams.2015.144">Williams & Swedo, 2015</a>). The first PANDAS treatment trials were based on the premise that symptom onset and exacerbations were a direct result of anti-<i>S. pyogenes</i> /anti-brain cross-reactive antibodies—if you could remove/inactivate the antibodies, the symptoms should improve (<a class="bibr" href="#pandas.REF.swedo.1998.264" rid="pandas.REF.swedo.1998.264">Swedo S. E., et al., 1998</a>; <a class="bibr" href="#pandas.REF.swedo.2001.419" rid="pandas.REF.swedo.2001.419">Swedo, Garvey, Snider, Hamilton, & Leonard, 2001</a>; <a class="bibr" href="#pandas.REF.swedo.2004.907" rid="pandas.REF.swedo.2004.907">Swedo, Leonard, & Rapoport, 2004</a>). A three-armed randomized controlled trial was designed to test this hypothesis by comparing therapeutic plasmapheresis (TPE), intravenous immunoglobulin (IVIG), and sham IVIG (placebo, masked to appear identical to active treatment) (<a class="bibr" href="#pandas.REF.perlmutter.1999.1153" rid="pandas.REF.perlmutter.1999.1153">Perlmutter, et al., 1999</a>). IVIG and TPE produced dramatic improvements in OC symptom severity (by 45% and 58%, respectively) within one month of completing treatment, while the sham IVIG had no discernible effect (despite 9 of the 10 subjects who received the placebo guessing it was “the active treatment” two days after completing the infusions) (<a class="bibr" href="#pandas.REF.perlmutter.1999.1153" rid="pandas.REF.perlmutter.1999.1153">Perlmutter, et al., 1999</a>). Treatment gains were maintained for at least one year. These results were comparable to those seen in a trial that compared TPE and IVIG against prednisone for treatment of SC (<a class="bibr" href="#pandas.REF.garvey.2005.424" rid="pandas.REF.garvey.2005.424">Garvey, Snider, Leitman, Werden, & Swedo, 2005</a>), and led the American Society of Apheresis to include TPE as a Category I first-line treatment option for PANDAS and SC. TPE did not benefit patients with non-PANDAS OCD (<a class="bibr" href="#pandas.REF.lougee.2000.1120" rid="pandas.REF.lougee.2000.1120">Lougee, Perlmutter, Nicolson, Garvey, & Swedo, 2000</a>) and IVIG did not improve non-PANDAS tic disorders (<a class="bibr" href="#pandas.REF.hoekstra.2004.537" rid="pandas.REF.hoekstra.2004.537">Hoekstra, Minderaa, & Kallenberg, 2004</a>).These findings imply that the positive changes observed in PANDAS patients may be attributable to the immunomodulatory actions of the treatments, rather than to a general therapeutic or placebo response to the invasive procedures. Moreover, the reduction in antineuronal antibody levels in TPE-treated individuals paralleled symptom relief, lending credence to the original hypothesis.</p><p>In a subsequent double-blind controlled trial, IVIG was compared to a placebo in a group of 35 patients carefully diagnosed with PANDAS (<a class="bibr" href="#pandas.REF.williams.2016.860" rid="pandas.REF.williams.2016.860">Williams, et al., 2016</a>). After six weeks, the IVIG group (n=17) showed a larger average reduction in OCD severity than the placebo group (n=18), although the difference did not reach statistical significance. Proceeding with open-label IVIG treatment led to a 50% reduction in OCD severity, with these improvements persisting over a year-long follow-up. While the lack of a control group in the open-label phase makes the significance of these findings unclear, the sustained improvements are noteworthy, as they are not typical for effects derived solely from study procedures and suggest a probable therapeutic effect of IVIG (<a class="bibr" href="#pandas.REF.leon.2018.637" rid="pandas.REF.leon.2018.637">Leon, et al., 2018</a>).</p><p>In addition to the two controlled trials, there have been a number of case reports and open-label treatment series published that provide additional support for the benefits of TPE (<a class="bibr" href="#pandas.REF.elia.2005.1145" rid="pandas.REF.elia.2005.1145">Elia, et al., 2005</a>; <a class="bibr" href="#pandas.REF.giedd.1996.913" rid="pandas.REF.giedd.1996.913">Giedd, Rapoport, Leonard, Richter, & Swedo, 1996</a>; <a class="bibr" href="#pandas.REF.latimer.2015.70" rid="pandas.REF.latimer.2015.70">Latimer, L'Etoile, Seidlitz, & Swedo, 2015</a>; <a class="bibr" href="#pandas.REF.prus.2022.597" rid="pandas.REF.prus.2022.597">Prus, Weidner, & Alquist, 2022</a>; <a class="bibr" href="#pandas.REF.tucker.1996.1684" rid="pandas.REF.tucker.1996.1684">Tucker, et al., 1996</a>) and IVIG in PANDAS (<a class="bibr" href="#pandas.REF.frankovich.2017.574" rid="pandas.REF.frankovich.2017.574">Frankovich, et al., 2017</a>; <a class="bibr" href="#pandas.REF.gerardi.2015.93" rid="pandas.REF.gerardi.2015.93">Gerardi, Casadonte, Patel, & Murphy, 2015</a>; <a class="bibr" href="#pandas.REF.hachiya.2013.670" rid="pandas.REF.hachiya.2013.670">Hachiya, et al., 2013</a>; <a class="bibr" href="#pandas.REF.hajjari.2022.535" rid="pandas.REF.hajjari.2022.535">Hajjari, et al., 2022</a>; <a class="bibr" href="#pandas.REF.kovacevic.2015.65" rid="pandas.REF.kovacevic.2015.65">Kovacevic, Grant, & Swedo, 2015</a>; <a class="bibr" href="#pandas.REF.melamed.2021.118" rid="pandas.REF.melamed.2021.118">Melamed, et al., 2021</a>). One of the largest of these open-label studies came from Italy, where 34 children with severe PANDAS with evidence of streptococcal infection were treated with IVIG resulting in diminished symptoms or complete remission in 29 of these patients (<a class="bibr" href="#pandas.REF.pavone.2018.854" rid="pandas.REF.pavone.2018.854">Pavone, et al., 2018</a>). However, symptoms resurfaced in five children after undergoing the third IVIG cycle. Despite the accumulating data from scores of patients, the absence of clear superiority of IVIG over placebo in the Yale-NIMH controlled trial raises ongoing questions about the benefits of IVIG in the treatment of PANDAS. Answers may be provided by a large double-blind placebo-controlled trial of IVIG currently underway in the U.S., Sweden and Italy, with results expected late in 2024 (<a class="bibr" href="#pandas.REF173" rid="pandas.REF173">National Library of Medicine, 2024</a>). In the interim, the U.S. PANS/PANDAS Clinical Research Consortium recommends that TPE and IVIG be reserved for use in severely ill children, particularly those at risk of self-harm (<a class="bibr" href="#pandas.REF.frankovich.2017.574" rid="pandas.REF.frankovich.2017.574">Frankovich, et al., 2017</a>). For mild-moderately ill children, corticosteroids, or non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen and naproxen) can provide significant symptomatic relief (<a class="bibr" href="#pandas.REF.brown.2017.619" rid="pandas.REF.brown.2017.619">Brown, et al., 2017</a>; <a class="bibr" href="#pandas.REF.spartz.2017.652" rid="pandas.REF.spartz.2017.652">Spartz, et al., 2017</a>). In addition to immunomodulatory therapies to address immune abnormalities, it is important to provide all PANDAS patients with symptomatic relief by utilizing standard psychiatric and behavioral interventions, such as anti-obsessional or anti-anxiety medications, cognitive-behavior therapy, and family supports (<a class="bibr" href="#pandas.REF.thienemann.2017.566" rid="pandas.REF.thienemann.2017.566">Thienemann, et al., 2017</a>).</p></div><div id="pandas.Epidemiological_and_Clinical_Evid"><h3>Epidemiological and Clinical Evidence of an Etiologic Role for <i>S. pyogenes</i> in PANDAS</h3><p>Population-based and medical records-based epidemiologic surveys are an important step in establishing a relationship between <i>S. pyogenes</i> infections and disease onset in PANDAS. To date, epidemiologic research has been hampered by the lack of a diagnostic code for PANDAS, which means that investigators must utilize pediatric cases of “obsessive-compulsive disorder” and “tic disorder” as proxies. In at least one OCD clinic, PANDAS cases represent only 5% of youth with a lifetime OCD diagnosis (<a class="bibr" href="#pandas.REF.jaspersfayer.2017.332" rid="pandas.REF.jaspersfayer.2017.332">Jaspers-Fayer, et al., 2017</a>), and in a large tic disorders clinic, acute-onset was reported by only 10% of patients (<a class="bibr" href="#pandas.REF.singer.2000.380" rid="pandas.REF.singer.2000.380">Singer, Giuliano, Zimmerman, & Walkup, 2000</a>). Even if PANDAS cases constitute one-fourth of pediatric OCD/tic disorder patients in a clinical database (<a class="bibr" href="#pandas.REF.swedo.1998.264" rid="pandas.REF.swedo.1998.264">Swedo, et al., 1998</a>; <a class="bibr" href="#pandas.REF.swedo.2004.907" rid="pandas.REF.swedo.2004.907">Swedo, Leonard, & Rapoport, 2004</a>), a temporal relationship between <i>S. pyogenes</i> and symptom onset in PANDAS might be obscured by the lack of a <i>S. pyogenes</i>-symptom association in the larger fraction of non-PANDAS OCD/tics cases. Thus, it was not surprising that Schrag and colleagues reported finding no association between “strep” and OCD/tics in a large UK medical database (<a class="bibr" href="#pandas.REF.schrag.2009.1256" rid="pandas.REF.schrag.2009.1256">Schrag, et al., 2009</a>). The study has been widely cited as evidence “refuting the hypothesized <i>S. pyogenes</i>-PANDAS relationship”, e.g. (<a class="bibr" href="#pandas.REF.gerland.2019.325" rid="pandas.REF.gerland.2019.325">Gerland, et al., 2019</a>; <a class="bibr" href="#pandas.REF.gilbert.2018.243" rid="pandas.REF.gilbert.2018.243">Gilbert, Mink, & Singer, 2018</a>). However, in actuality, the negative findings were more likely due to flaws in the study design; among others, the age range was set at 2–24 years and the mean age of subjects was 16 years, well past the prepubertal onset required for PANDAS; acuity of onset was not assessed; the intervals of interest were set at 2 years and 5 years, which precluded assessment of a causal role for <i>S. pyogenes</i> in the onset of tics or OCD and also increased the number of “controls” positive for a strep-OCD/tics relationship; and “strep” infections were defined by a list of 71 diagnostic codes, of which 27 were possibly relevant to a <i>S. pyogenes</i> infection (e.g, “has a sore throat”, acute tonsillitis, pyoderma) while the others were clearly not germane, (e.g., “normal/healthy tonsils”, “pyoderma chancriforme,” “pneumonia due to group B streptococcus,” and others, as seen in <a class="figpopup" href="/books/NBK607260/figure/pandas.F3/?report=objectonly" target="object" rid-figpopup="figpandasF3" rid-ob="figobpandasF3">Figure 3</a> (<a class="bibr" href="#pandas.REF.schrag.2009.1256" rid="pandas.REF.schrag.2009.1256">Schrag, et al., 2009</a>).</p><p>A study by Schrag and colleagues was conducted in collaboration with the European Multicenter Tics in Children Study (EMTICS) and was able to correct many of the first investigation’s deficiencies, but introduced a significant ascertainment bias when they chose to limit access to antibiotic treatment for study participants, thus discouraging enrolment by children at high risk for <i>S. pyogenes</i>-triggered symptoms (<a class="bibr" href="#pandas.REF.schrag.2022.e1175" rid="pandas.REF.schrag.2022.e1175">Schrag, et al., 2022</a>). Gupta, et al. (<a class="bibr" href="#pandas.REF.gupta.2022.445" rid="pandas.REF.gupta.2022.445">Gupta, et al., 2022</a>), in a letter to the editor about the EMTICS study, stated that the multicenter investigation did not reach its recruitment goal of 500 children (actual n = 259) and therefore, did not have sufficient power to detect a link between <i>S. pyogenes</i> infections and tic onset disorders in children at genetic risk (<a class="bibr" href="#pandas.REF.schrag.2022.e1175" rid="pandas.REF.schrag.2022.e1175">Schrag, et al., 2022</a>). In addition, many parents/children did not participate because antibiotics would be limited in the study. The editorial by Gupta, et al. states that the large group of doctors writing the editorial had observed the “transformative” effects of antibiotics in PANDAS. The negative selection bias eliminated some families who perceived their child was high risk, and who wanted access to antibiotics during the EMTICS trial. These reasons plus the recruitment of only children with genetic risk of tics limited the type of patient in the trial. Further, study of autoimmune or infectious predisposition was not considered in the trial (<a class="bibr" href="#pandas.REF.gupta.2022.445" rid="pandas.REF.gupta.2022.445">Gupta, et al., 2022</a>).</p><p>In contrast to these negative studies, several epidemiologic surveys have found a strong correlation between the onset of tics/OCD and <i>S. pyogenes</i> infections. An analysis of administrative data from a health maintenance organization in the Seattle region examined 144 newly diagnosed cases of Tourette syndrome (TS) and OCD/tics, which were compared with 609 controls. This study revealed a marked association, with a 13-fold increase in the likelihood of having had a prior <i>S. pyogenes</i> infection, diagnosed either three months or one year before the initial symptoms of TS appeared. Furthermore, the data indicated that the risk of developing TS was significantly heightened by the presence of multiple <i>S. pyogenes</i> infections in the 12 months preceding symptom onset (<a class="bibr" href="#pandas.REF.mell.2005.56" rid="pandas.REF.mell.2005.56">Mell, Davis, & Owens, 2005</a>). A strong association with a prior <i>S. pyogenes</i> infection also was found in a U.S. national health insurance study, where 479 cases of OCD, tics, and TS were matched with 3647 controls. Subjects with newly diagnosed OCD or tic disorders were more likely than controls to have had a <i>S. pyogenes</i> infection diagnosed in the previous year (odds ratio 1.53, 95% confidence interval 1.29–2,15); interestingly, youth with ADHD or major depressive disorder were also more likely to have had a prior <i>S. pyogenes</i> infection (Odds ratios of 1.20 and 1.63, respectively), although directionality of the association cannot be determined (<a class="bibr" href="#pandas.REF.leslie.2008.1166" rid="pandas.REF.leslie.2008.1166">Leslie, et al., 2008</a>).</p><p>School-based studies are close approximations of population-based epidemiology and have the added advantage of providing opportunities for direct observations. Snider, et al. conducted monthly in-person classroom observations of 553 children (aged 5–12 years) and found the monthly point prevalence of motor tics ranged from 3.2% to 9.6%, with an overall frequency of 24.4% for the seven months observation period of November–June. Of interest, the highest rates were seen during the winter months of November through February, when <i>S. pyogenes</i> infections were most frequent in the community (<a class="bibr" href="#pandas.REF.snider.2002.331" rid="pandas.REF.snider.2002.331">Snider, et al., 2002</a>). Murphy and colleagues enrolled 693 children (ages 3–12 years) into a systematic longitudinal study (<a class="bibr" href="#pandas.REF.murphy.2007.279" rid="pandas.REF.murphy.2007.279">Murphy, et al., 2007</a>). Data were collected monthly between October and May at three Putnam County, Florida elementary schools to determine point prevalence of tics, behaviors (11 specific, observable activities such as facial grimacing, fidgeting, etc.), choreiform movements, and <i>S. pyogenes</i> infections (a positive throat culture obtained concurrently with the observations). Strong correlations were found between <i>S. pyogenes</i> infections and behaviors (relative risk (RR) of 1.71, p<0.0001), with more behaviors and <i>S. pyogenes</i> infections found in the fall months (p<0.0001) compared with winter/spring months. Children with repeated <i>S. pyogenes</i> infections (n=64) showed the highest rates of behaviors and Touwen-type choreiform movements (p=0.005) (<a class="bibr" href="#pandas.REF.murphy.2007.279" rid="pandas.REF.murphy.2007.279">Murphy, et al., 2007</a>). The latter finding is particularly interesting in light of a Lewis rat model and mouse model of PANDAS that found behavioral/motor disturbances after repeated <i>S. pyogenes</i> immunization (<a class="bibr" href="#pandas.REF.brimberg.2012.2076" rid="pandas.REF.brimberg.2012.2076">Brimberg, et al., 2012</a>; <a class="bibr" href="#pandas.REF.rafeek.2021.151" rid="pandas.REF.rafeek.2021.151">Rafeek, et al., 2021</a>; <a class="bibr" href="#pandas.REF.rafeek.2022.653" rid="pandas.REF.rafeek.2022.653">Rafeek, et al., 2022</a>) or infection (<a class="bibr" href="#pandas.REF.hoffman.2004.1780" rid="pandas.REF.hoffman.2004.1780">Hoffman, Hornig, Yaddanapudi, Jabado, & Lipkin, 2004</a>), respectively. Transfer of serum IgG was also found to lead to symptom onset in rats or mice (<a class="bibr" href="#pandas.REF.lotan.2014a.249" rid="pandas.REF.lotan.2014a.249">Lotan, et al., 2014a</a>; <a class="bibr" href="#pandas.REF.yaddanapudi.2010.712" rid="pandas.REF.yaddanapudi.2010.712">Yaddanapudi, et al., 2010</a>).</p><p>Clinical cohorts represent “convenience samples” that have epidemiologic limitations (due to the lack of generalizability to the population of healthy children) but offer opportunities for between-group comparisons of carefully diagnosed patient cohorts. One such study evaluated <i>S. pyogenes</i> infections, anti-streptococcal, and anti-basal ganglia antibody titers in 168 Italian TS children and a comparison group of 177 patients with epileptic or sleep disorders (<a class="bibr" href="#pandas.REF.martino.2011.951" rid="pandas.REF.martino.2011.951">Martino, et al., 2011</a>). They found a higher frequency of <i>S. pyogenes</i> infections (8% vs 2%; p=0.009), higher anti-streptolysin O (ASO) titers (246 vs 125, p<0.001), and higher anti-basal ganglia antibodies (ABGA) frequency (25% vs 8%; p<0.001) in TS patients than controls. However, new infections or newly positive ABGA titers did not predict clinical exacerbations. A small cross-sectional study in a tic disorders clinic measured ASO, anti-DNAseB and ABGA titers in 41 children with TS/ADHD (mean age 11.3 yrs, mean age of tic onset = 6.5 yrs) and 38 tic-free controls (mean age 12.2 yrs). No significant differences were found between patients and controls, but higher ASO titers were noted in 14 TS children with ADHD, as compared to the non-ADHD TS group (n=14) (<a class="bibr" href="#pandas.REF.loiselle.2003.119" rid="pandas.REF.loiselle.2003.119">Loiselle, Wendlandt, Rohde, & Singer, 2003</a>). A subsequent study in the same clinic evaluated ABGA titers in 30 children with TS, 30 children with “PANDAS” and 30 controls. Sera from TS and PANDAS patients had more antibody positivity and a higher immunofluorescence against human basal ganglia tissue than controls, but the sample sizes were too small to demonstrate a statistical significance between immunofluorescent reactivity and diagnosis (<a class="bibr" href="#pandas.REF.morris.2009.45" rid="pandas.REF.morris.2009.45">Morris, Pardo-Villamizar, Gause, & Singer, 2009</a>).</p><p>Perrin, et al., enrolled 814 children aged 4 to 11 years in a 12-week-long prospective pediatric clinic-based study conducted between October 2001 to June 2002 in Rochester NY. Symptomatic children with <i>S. pyogenes</i> infections (n=399 of 411<i>S. pyogenes</i> positive subjects) were treated with antibiotics; the <i>S. pyogenes</i> uninfected group included 403 children, of whom 207 had pharyngitis with negative throat culture and 196 were seen for a well-child check (<a class="bibr" href="#pandas.REF.perrin.2004.848" rid="pandas.REF.perrin.2004.848">Perrin, et al., 2004</a>). At baseline, parents of ill children (399 <i>S. pyogenes</i>+ and 207 <i>S. pyogenes</i>- pharyngitis) reported more PANDAS-related symptoms than parents of well children (n=196), specifically “harder time paying attention,” “more fidgety or restless,” “unusually clingy/harder time with separation,” new presence of vocalizations, new motor tics, and “unusual toilet paper wiping/bathroom rituals.” At 12 weeks, the rate of tics and vocalizations in the <i>S. pyogenes</i>-infection group had decreased to that of the well children, but ratings of several PANDAS-related symptoms remained higher in the <i>S. pyogenes</i>+ cohort than in the well children group, although the only ones reaching statistical significance were “more sick with worry” (OR 4.2) and “unusual fears (OR 5.6) (<a class="bibr" href="#pandas.REF.perrin.2004.848" rid="pandas.REF.perrin.2004.848">Perrin, et al., 2004</a>). The authors concluded that treated <i>S. pyogenes</i> infections were not a significant cause of PANDAS-related symptoms, as is true for rheumatic fever, but cautioned that the study was unable to address the primary question of interest in PANDAS—do unrecognized/untreated <i>S. pyogenes</i> infections play a role in symptom onset as they do in SC and other manifestations of acute rheumatic fever (<a class="bibr" href="#pandas.REF.garvey.1998.413" rid="pandas.REF.garvey.1998.413">Garvey, Giedd, & Swedo, 1998</a>; <a class="bibr" href="#pandas.REF.swedo.1994.1788" rid="pandas.REF.swedo.1994.1788">Swedo S. E., 1994</a>). Thus, it is important to raise the question, “Do symptom-free or carriers of <i>S. pyogenes</i> have a greater potential to develop PANDAS?”. There is some indication that SC can be triggered by symptom-less <i>S. pyogenes</i> infections and that rheumatic fever can relapse in such patients, but unfortunately, there is no thorough, rigorous study that questions whether carriers, immune or otherwise, are at risk of developing rheumatic fever or scarlet fever.</p><p>In a longitudinal clinic-based study, the relationship between <i>S. pyogenes</i> infections and symptom exacerbations in 25 children with OCD and/or tic disorder (mean age 10.5 yrs) were evaluated every 6 weeks for at least six consecutive clinic visits (range 9–22 months of follow-up) (<a class="bibr" href="#pandas.REF.murphy.2004.61" rid="pandas.REF.murphy.2004.61">Murphy, et al., 2004</a>). Fifteen children with dramatic symptom fluctuations were compared against those without large symptom variability (n=10) and were found to have higher <i>S. pyogenes</i> titers (p=0.001) throughout the study period. A positive correlation between <i>S. pyogenes</i> titers and OCD severity rating changes (p=0.013) was found in the high variability group, but not in the more stable cohort. The study is unique in that it included measurements of antibodies directed against the streptococcal capsular polysaccharide (ACHO titers), a key factor in acute rheumatic fever (<a class="bibr" href="#pandas.REF.cunningham.2012.408" rid="pandas.REF.cunningham.2012.408">Cunningham, 2012</a>; <a class="bibr" href="#pandas.REF.martins.2008.445" rid="pandas.REF.martins.2008.445">Martins, et al., 2008</a>). The ACHO titers were found to rise in conjunction with the ASO and anti-DNaseB titers but remained elevated for a longer period of time (<a class="bibr" href="#pandas.REF.murphy.2004.61" rid="pandas.REF.murphy.2004.61">Murphy, et al., 2004</a>). The significance of this difference is unknown, but it does serve as a reminder that ASO and anti-DNaseB titers are only a proxy for the cross-reactive antibodies thought to be responsible for post-<i>S. pyogenes</i> neuropsychiatric sequelae. In ARF patients, ASO and DNase B antibody levels decreased by 45% by week 4 and continued to drop (<a class="bibr" href="#pandas.REF.martins.2008.445" rid="pandas.REF.martins.2008.445">Martins, et al., 2008</a>). This trend, coupled with a common 18- to20-day latency period following pharyngitis (<a class="bibr" href="#pandas.REF.alsaeid.1998.295" rid="pandas.REF.alsaeid.1998.295">Alsaeid & Majeed, 1998</a>; <a class="bibr" href="#pandas.REF.veasy.1997.400" rid="pandas.REF.veasy.1997.400">Veasy & Hill, 1997</a>), can complicate achieving an accurate and timely diagnosis.</p><p>The studies by Kurlan, Leckman, Singer, and the U.S. Tourette Syndrome Study group performed interconnected studies, spread across six U.S. sites, aimed to investigate the link between <i>S. pyogenes</i> (Group A Streptococcus) infections and symptom exacerbations over a 2-year period (<a class="bibr" href="#pandas.REF.kurlan.2008.1188" rid="pandas.REF.kurlan.2008.1188">Kurlan, Johnson, Kaplan, & Tourette Syndrome Study Group, 2008</a>; <a class="bibr" href="#pandas.REF.leckman.2011.108" rid="pandas.REF.leckman.2011.108">Leckman, et al., 2011</a>). Serial ASO, anti-DNAse B titers, and throat cultures were the mainstays of <i>S. pyogenes</i> detection for these inter-connected studies. Despite standardized testing, their findings—reported in separate papers with small sample sizes—showed an unexpectedly low rate of exacerbations and <i>S. pyogenes</i> infections (<a class="bibr" href="#pandas.REF.morris.2009.45" rid="pandas.REF.morris.2009.45">Morris, Pardo-Villamizar, Gause, & Singer, 2009</a>; <a class="bibr" href="#pandas.REF.singer.2008.1198" rid="pandas.REF.singer.2008.1198">Singer, Gause, Morris, & Lopez, 2008</a>). This outcome, potentially linked to methodological limitations and lack of statistical power, hindered the studies' ability to establish a significant association between <i>S. pyogenes</i> and PANDAS symptoms (<a class="bibr" href="#pandas.REF.dale.2005.785" rid="pandas.REF.dale.2005.785">Dale, 2005</a>).</p><p>The E.L. Kaplan, MN laboratory conducted all study-related <i>S. pyogenes</i> testing on sera and duplicate throat swabs. However, the monthly throat cultures were locally sourced, and any positive findings could be treated by the child’s healthcare provider, which potentially reduced the incidence of post-streptococcal complications. Despite the singularity of methods, the results were reported separately in two papers (<a class="bibr" href="#pandas.REF.kurlan.2008.1188" rid="pandas.REF.kurlan.2008.1188">Kurlan, Johnson, Kaplan, & Tourette Syndrome Study Group, 2008</a>; <a class="bibr" href="#pandas.REF.leckman.2011.108" rid="pandas.REF.leckman.2011.108">Leckman, et al., 2011</a>), which led to sample sizes that lacked sufficient statistical power to identify a significant link between <i>S. pyogenes</i> and rate of exacerbations; however, rates appear to be comparable to previously published reports. <a class="bibr" href="#pandas.REF.kurlan.2008.1188" rid="pandas.REF.kurlan.2008.1188">Kurlan et al (2008)</a> found 0.56/0.43 exacerbations/<i>S. pyogenes</i> infections (respectively) per person-year in PANDAS cases and 0.28/0.13 person-year for control subjects, while <a class="bibr" href="#pandas.REF.leckman.2011.108" rid="pandas.REF.leckman.2011.108">Leckman et al (2011)</a> reported finding 0.45/0.36 exacerbations/<i>S. pyogenes</i> infections per person-year for PANDAS cases and 0.42/0.39 for controls (<a class="bibr" href="#pandas.REF.kurlan.2008.1188" rid="pandas.REF.kurlan.2008.1188">Kurlan, Johnson, Kaplan, & Tourette Syndrome Study Group, 2008</a>; <a class="bibr" href="#pandas.REF.leckman.2011.108" rid="pandas.REF.leckman.2011.108">Leckman, et al., 2011</a>). These results are quite similar to those reported previously by Leckman’s group (<a class="bibr" href="#pandas.REF.lin.2002.1070" rid="pandas.REF.lin.2002.1070">Lin, et al., 2002</a>). In that study, longitudinal evaluations with monthly evaluations were used to define thresholds for symptom exacerbations among 64 patients [tics only (n=40), OCD only (n=7) or tics+OCD (n=17)] and investigators found 29 of 702 monthly ratings met criteria for exacerbations, which equates to approximately 0.41 exacerbations per “person-year” (number of monthly evaluations divided by 12) (<a class="bibr" href="#pandas.REF.lin.2002.1070" rid="pandas.REF.lin.2002.1070">Lin, et al., 2002</a>). A subsequent investigation of 47 Yale clinic patients with TS and/or OCD and 19 healthy controls reported that the rate of exacerbations was 0.56 per patient per year and there were 0.42 <i>S. pyogenes</i> infections per TS/OCD patient per year and 0.28 <i>S. pyogenes</i> infections per control per year (<a class="bibr" href="#pandas.REF.luo.2004.e578" rid="pandas.REF.luo.2004.e578">Luo, et al., 2004</a>). Given the comparability of rates in these studies to those of found by Kurlan, et al. (<a class="bibr" href="#pandas.REF.kurlan.2008.1188" rid="pandas.REF.kurlan.2008.1188">Kurlan, Johnson, Kaplan, & Tourette Syndrome Study Group, 2008</a>), it is curious that the investigators decided to move ahead with publication of preliminary (so-called “negative”) results, rather than waiting to recruit a sample large enough to address the study’s goals (<a class="bibr" href="#pandas.REF.kurlan.2008.1188" rid="pandas.REF.kurlan.2008.1188">Kurlan, Johnson, Kaplan, & Tourette Syndrome Study Group, 2008</a>). At the least, Kurlan’s preliminary data should have been analyzed in combination with those later reported by Leckman, et al. (<a class="bibr" href="#pandas.REF.leckman.2011.108" rid="pandas.REF.leckman.2011.108">Leckman, et al., 2011</a>) so that the sample size would have been closer to that required to search for a <i>S. pyogenes</i>-exacerbation relationship (<a class="bibr" href="#pandas.REF.leckman.2011.108" rid="pandas.REF.leckman.2011.108">Leckman, et al., 2011</a>). As it is, we know only that both reports were under-powered to detect such a <i>S. pyogenes</i>-symptom association. Unfortunately, they’ve been interpreted by numerous authors as “strong evidence suggesting the absence of an important role for GABHS” (<a class="bibr" href="#pandas.REF.leckman.2011.108" rid="pandas.REF.leckman.2011.108">Leckman, et al., 2011</a>; <a class="bibr" href="#pandas.REF.shulman.2009.127" rid="pandas.REF.shulman.2009.127">Shulman, 2009</a>). A related study by Johnson, et al. (<a class="bibr" href="#pandas.REF.johnson.2010.481" rid="pandas.REF.johnson.2010.481">Johnson, Kurlan, Leckman, & Kaplan, 2010</a>) examined a subset of longitudinal samples from the Kurlan/Leckman cohort and revealed that several of the exacerbations presumed to be <i>S. pyogenes</i>-negative were actually <i>S. pyogenes</i>-positive (<a class="bibr" href="#pandas.REF.johnson.2010.481" rid="pandas.REF.johnson.2010.481">Johnson, Kurlan, Leckman, & Kaplan, 2010</a>). The investigators found that a true rise in anti-streptococcal antibodies may occur at levels below the upper limit of normal (ULN) used in many studies and recommend the use of serial titers, rather than absolute levels, as a true marker of <i>S. pyogenes</i> infection. The results of the study also highlighted the importance of using at least two antibodies (ASO and anti-DNase B) for the diagnosis of new infection, since antibody responses differ by infecting <i>S. pyogenes</i> organism. Results from Murphy, et al. showed that even the combination of ASO and antiDNaseB titers may not be sufficient to detect all immunologically active <i>S. pyogenes</i> infections (<a class="bibr" href="#pandas.REF.murphy.2004.61" rid="pandas.REF.murphy.2004.61">Murphy, et al., 2004</a>).</p><p>Johnson and colleagues also demonstrated that a true infection with a significant antibody response can be associated with cultures showing <10 colonies per plate, which demonstrates that many infections would be unidentified without longitudinal observation or specialized cultures (as described above) (<a class="bibr" href="#pandas.REF.johnson.2010.481" rid="pandas.REF.johnson.2010.481">Johnson, Kurlan, Leckman, & Kaplan, 2010</a>). Using this knowledge to guide a reanalysis of combined datasets from Kurlan, et al. and Leckman, et al. might provide answers to questions about the etiologic role of <i>S. pyogenes</i> in PANDAS (<a class="bibr" href="#pandas.REF.kurlan.2008.1188" rid="pandas.REF.kurlan.2008.1188">Kurlan, Johnson, Kaplan, & Tourette Syndrome Study Group, 2008</a>; <a class="bibr" href="#pandas.REF.leckman.2011.108" rid="pandas.REF.leckman.2011.108">Leckman, et al., 2011</a>). Cardona & Orefici utilized many of the methods recommended by Johnson, et al. to conduct a case-control study of 150 Italian children (<a class="bibr" href="#pandas.REF.cardona.2001.71" rid="pandas.REF.cardona.2001.71">Cardona & Orefici, 2001</a>; <a class="bibr" href="#pandas.REF.johnson.2010.481" rid="pandas.REF.johnson.2010.481">Johnson, Kurlan, Leckman, & Kaplan, 2010</a>). They were examined between March 1996 and November 1998 for sudden onset, recrudescence, or protracted duration of their tic disorders. The controls were 150 healthy children without tics. The study found that 38% of cases (in comparison with 2% of controls) had ASO titers higher than 500 IU; their mean ASO titer was 434 IU, in comparison with 155 IU in the controls (p<0.01). Moreover, 17% had a throat swab positive for <i>S. pyogenes</i> at the time of initial evaluation. None of the patients had clinical evidence of pharyngitis and if analyzed by standard methods, several of the cultures would have been called “negative” because of the small number of <i>S. pyogenes</i> colonies on the culture plate. As a result, an old pour plate method was used (<a class="bibr" href="#pandas.REF.taranta.1971.125" rid="pandas.REF.taranta.1971.125">Taranta & Moody, 1971</a>) that gave better results than the one routinely used for pharyngitis. See <a class="figpopup" href="/books/NBK607260/figure/pandas.F8/?report=objectonly" target="object" rid-figpopup="figpandasF8" rid-ob="figobpandasF8">Figure 8</a><b>.</b> (<a class="bibr" href="#pandas.REF.johnson.1997.1203" rid="pandas.REF.johnson.1997.1203">Johnson, Karabatsos, & Lanciotti, 1997</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpandasF8" co-legend-rid="figlgndpandasF8"><a href="/books/NBK607260/figure/pandas.F8/?report=objectonly" target="object" title="Figure 8. " class="img_link icnblk_img figpopup" rid-figpopup="figpandasF8" rid-ob="figobpandasF8"><img class="small-thumb" src="/books/NBK607260/bin/pandas-Image008.gif" src-large="/books/NBK607260/bin/pandas-Image008.jpg" alt="Figure 8. . Differences in Culture Technique by Blood Agar Plating of Group A Streptococci in Culture: Demonstrating the difficulties encountered when attempting to culture the throat or other samples from humans on a Blood Agar Plate." /></a><div class="icnblk_cntnt" id="figlgndpandasF8"><h4 id="pandas.F8"><a href="/books/NBK607260/figure/pandas.F8/?report=objectonly" target="object" rid-ob="figobpandasF8">Figure 8. </a></h4><p class="float-caption no_bottom_margin">Differences in Culture Technique by Blood Agar Plating of Group A Streptococci in Culture: Demonstrating the difficulties encountered when attempting to culture the throat or other samples from humans on a Blood Agar Plate. On the blood agar plate where <a href="/books/NBK607260/figure/pandas.F8/?report=objectonly" target="object" rid-ob="figobpandasF8">(more...)</a></p></div></div><p>The authors note that the throat must be swabbed properly to ensure that <i>S. pyogenes</i> bacteria are captured by the swab without simultaneously acquiring excess saprophytic flora that could obscure <i>S. pyogenes</i> colonies. Failing to do so could result in a negative throat culture that is a misrepresentation of the child’s clinical condition.</p><p>Cardona & Orefici raise another point for consideration: the role that intracellular <i>S. pyogenes</i> bacteria may play in PANDAS and related conditions. The potential of intracellular streptococci to confound relationship studies is quite important. Transient and persistent intracellar infection is clearly integral to acute <i>S. pyogenes</i> infections, and may influence the results of throat cultures or rapid antigen-based tests. Importantly and in this regard, M-protein–expressing <i>S. pyogenes</i> strains can survive after phagocytosis by human neutrophils (<a class="bibr" href="#pandas.REF.staali.2003.253" rid="pandas.REF.staali.2003.253">Staali, Mörgelin, Björck, & Tapper, 2003</a>) and the surface M-anchored protein has been identified as the pivotal factor that affects the phagosomal maturation in macrophages (<a class="bibr" href="#pandas.REF.hertz_n.2012.e35218" rid="pandas.REF.hertz_n.2012.e35218">Hertzén, et al., 2012</a>). After a replicative phase, <i>S. pyogenes</i> destroy the host cell to egress and then can infect new cells, thus persisting and serving as an antigenic stimulus for an extended period of time as well as hide within cells and create infections that are potentially difficult to diagnose. It may also account for the intermittent presence of the same serotype in the throat of tic patients on repeated cultures and possibly explain the high percentage of “carriers” seen in some studies after treatment (<a class="bibr" href="#pandas.REF.pichichero.1999a.624" rid="pandas.REF.pichichero.1999a.624">Pichichero, et al., 1999a</a>). Furthermore, hiding <i>S. pyogenes</i> in host cells are a useful niche to escape many antibiotic drugs used against <i>S. pyogenes</i> (such as penicillin, for instance) and these intracellular organisms would have a selective advantage based on their ability to enter and survive the course of antibiotics (<a class="bibr" href="#pandas.REF.kaplan.1981.326" rid="pandas.REF.kaplan.1981.326">Kaplan, Gastanaduy, & Huwe, 1981</a>; <a class="bibr" href="#pandas.REF.park.2003.2532" rid="pandas.REF.park.2003.2532">Park, Francis, Yu, & Cleary, 2003</a>). Further research should be done to determine if intracellular <i>S. pyogenes</i> organisms are the cause of a common problem observed in the management of PANDAS patients—children have an excellent response to antibiotic therapies but then relapse within 1–3 days of completing the course of therapy and fail to remit if the same antibiotic is reintroduced. The presence of intracellular <i>S. pyogenes</i> could be one of the reasons for such relapses, as well as antibiotic noncompliance; or other causes, such as the presence of staphylococcal strains destroying penicillin-based drugs with penicillinase.</p><p>A recent study by Hysmith and colleagues extends the cautions about methodology to serologic testing (<a class="bibr" href="#pandas.REF.hysmith.2017.187" rid="pandas.REF.hysmith.2017.187">Hysmith, et al., 2017</a>). In this collaborative investigation, serum samples and throat cultures were collected from 41 of the subjects followed prospectively for two years in the Kurlan/Leckman studies. The samples revealed 51 new <i>S. pyogenes</i> acquisitions that elicited an antibody response against at least 1 of the 31 antigens tested (13 shared <i>S. pyogenes</i> antigens and 18 type-specific M peptides). On average, the new <i>S. pyogenes</i> acquisitions provoked antibodies against 3.5 antigens with antibody responses to the homologous M peptide observed in 32 (63%) of the 51 episodes. Of note, only 67% of the new <i>S. pyogenes</i> infections provoked a rise in ASO and/or antiDNase B titers, which means that standard testing would miss one-third of the infections. And of greater concern, 65% of the new <i>S. pyogenes</i> infections were asymptomatic (no signs or symptoms of pharyngitis) and would not have come to clinical attention. With two-thirds of immunologically active acquisitions being asymptomatic in patients with OCD/tics/PANDAS, one must ask why the American Academy of Pediatrics(AAP) Committee on Infectious Diseases continues to recommend the following: “In the absence of acute clinical symptoms and signs of pharyngitis, <i>S. pyogenes</i> testing (by culture, antigen detection, or serology) is not recommended for such (PANDAS or PANS) patients (<a class="bibr" href="#pandas.REF241" rid="pandas.REF241">The Committee on Infectious Diseases, 2024</a>).” On the basis of the report by Hysmith and colleagues, and in keeping with the requirement that physicians should “First do no harm”, we would challenge the AAP recommendation by asking: “Where is the harm in obtaining a throat culture and treating with antibiotics: 1) if <i>S. pyogenes</i> positive? 2) if an asymptomatic <i>S. pyogenes</i> positive throat infection is responsible for the PANDAS symptomatology? 3) if a child is suffering impairing symptoms of OCD, tics, anxiety, suicidality or other symptoms in a disease we have proven to be similar to Sydenham chorea in acute rheumatic fever?” Prevention was the theme of the recent National Heart Lung and Blood Institute workshop on Acute rheumatic fever and rheumatic heart disease, and resulted in five new publications to end rheumatic fever and rheumatic heart disease including other group A streptococcal sequelae (<a class="bibr" href="#pandas.REF.baker.2023.e012467" rid="pandas.REF.baker.2023.e012467">Baker, et al., 2023</a>; <a class="bibr" href="#pandas.REF.fulurija.2023.e013534" rid="pandas.REF.fulurija.2023.e013534">Fulurija, et al., 2023</a>; <a class="bibr" href="#pandas.REF.karthikeyan.2023.e012468" rid="pandas.REF.karthikeyan.2023.e012468">Karthikeyan, et al., 2023</a>; <a class="bibr" href="#pandas.REF.rwebembera.2023.e012356" rid="pandas.REF.rwebembera.2023.e012356">Rwebembera, et al., 2023</a>; <a class="bibr" href="#pandas.REF.vervoort.2023.e012355" rid="pandas.REF.vervoort.2023.e012355">Vervoort, et al., 2023</a>). Although PANDAS is not considered to be a piece of rheumatic fever, it is likely a streptococcal sequelae related to Sydenham chorea as a “subgroup” stated earlier in this chapter. Both SC and PANDAS share similar anti-neuronal autoantibodies helpful in diagnosis, and symptoms of PANDAS have been shown to improve when the treatment regimen follows the rheumatic heart disease antibiotic prophylaxis protocol (<a class="bibr" href="#pandas.REF.lepri.2019.608" rid="pandas.REF.lepri.2019.608">Lepri, et al., 2019</a>). The studies described below attest to the importance of treatment with antibiotics in PANDAS. It is one of the anchor treatments along with immunomodulatory therapies, as well as psychiatric evaluation and therapy, as described in the treatment guidelines (<a class="bibr" href="#pandas.REF.cooperstock.2017.594" rid="pandas.REF.cooperstock.2017.594">Cooperstock, Swedo, Pasternack, & Murphy, 2017</a>; <a class="bibr" href="#pandas.REF.thienemann.2017.566" rid="pandas.REF.thienemann.2017.566">Thienemann, et al., 2017</a>; <a class="bibr" href="#pandas.REF.frankovich.2017.574" rid="pandas.REF.frankovich.2017.574">Frankovich, et al., 2017</a>; <a class="bibr" href="#pandas.REF.latimer.2015.70" rid="pandas.REF.latimer.2015.70">Latimer, L'Etoile, Seidlitz, & Swedo, 2015</a>; <a class="bibr" href="#pandas.REF.perlmutter.1999.1153" rid="pandas.REF.perlmutter.1999.1153">Perlmutter, et al., 1999</a>).</p></div></div><div id="pandas.The_Impact_of_Antibiotics_Treatme"><h2 id="_pandas_The_Impact_of_Antibiotics_Treatme_">The Impact of Antibiotics Treatment and Prophylaxis</h2><p>The first clinical investigation of PANDAS was conducted in a large pediatric practice in New York state by Murphy and Pichichero (<a class="bibr" href="#pandas.REF.murphy.2002.356" rid="pandas.REF.murphy.2002.356">Murphy & Pichichero, 2002</a>). Twelve children [(7 boys, 5 girls; mean age 7 yrs (range 5–11 yrs)] were prospectively evaluated after initial presentation of acute-onset OCD and mild symptoms and signs of <i>S. pyogenes</i> pharyngitis. (Of note, 7 of the 12 patients also had complaints of daytime urinary urgency and frequency without dysuria or fever; urinalysis/cultures revealed no signs of urinary tract infection.) Throat swabs from all twelve were <i>S. pyogenes</i> positive by rapid antigen detection and/or culture. The children were treated with antibiotics, which eradicated the <i>S. pyogenes</i> infections and produced complete remission of OCD and accompanying symptoms. Six of the twelve children had an OCD recurrence during the twelve months of follow-up, all of which were also associated with a positive <i>S. pyogenes</i> culture and responded to antibiotic treatment of the <i>S. pyogenes</i> infection (<a class="bibr" href="#pandas.REF.murphy.2002.356" rid="pandas.REF.murphy.2002.356">Murphy & Pichichero, 2002</a>). This study demonstrates the positive impact of prompt recognition and treatment of <i>S. pyogenes</i>-triggered neuropsychiatric symptoms. By quickly treating the sentinel episode with antibiotics, rapid remissions were enjoyed by all patients and none had seriously impairing recurrences and were thus spared the need for prolonged psychiatric treatments or aggressive immunotherapy. These findings were replicated and extended by Murphy, et al. in two controlled antibiotics trials (<a class="bibr" href="#pandas.REF.murphy.2015.14" rid="pandas.REF.murphy.2015.14">Murphy, et al., 2015</a>). In the first, 20 subjects with OCD or tics (acute onset not required) were randomized to receive placebo (n=11) or cefdinir (n=9) for 30 days. The Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) and Yale Global Tic Severity Scale (YGTSS) were used to assess primary outcomes. The group receiving cefdinir had notable improvements in both OCD symptoms and tics (decrease in OCD severity of 7.8 points and tics severity of 9.5 points), but small sample sizes and large inter-subject variability (large SD) precluded the improvements from reaching statistical significance, as the placebo group also showed minor improvements (OCD scores decreased by 4.7 points and tics by 0.13) (<a class="bibr" href="#pandas.REF.murphy.2015.14" rid="pandas.REF.murphy.2015.14">Murphy, et al., 2015</a>). The second trial compared a 30-day course of azithromycin against placebo in 31 youth with acute-onset OCD (18 active, 14 placebo). Azithromycin was superior to placebo in reducing OCD severity on the Clinical Global Impressions Severity scale (CGI-S OCD) and also had more “treatment responders” than the placebo group (7 vs 1). Side effects were mild, but azithromycin was associated with more loose or abnormal stools (p=0.009) and non-significant prolongation of the QTc on electrocardiography (<a class="bibr" href="#pandas.REF.calaprice.2018.92" rid="pandas.REF.calaprice.2018.92">Calaprice, Tona, & Murphy, 2018</a>).</p><p>In a large Italian study, investigators at three clinics collaborated to perform clinical-serological characterizations of 371 consecutively evaluated children, who were then treated with benzathine benylpenicillin (<a class="bibr" href="#pandas.REF.lepri.2019.608" rid="pandas.REF.lepri.2019.608">Lepri, et al., 2019</a>). All patients had a history of acute onset OCD and/or tics starting before puberty (mean age at onset = 6.4 yrs) and 74 (20%) were known to have had a preceding <i>S. pyogenes</i> infection. On average, children came for diagnosis two years later (mean age at diagnosis = 8.5 yrs). Antistreptolysin O (ASO) titers measured at first presentation were positive in 273 of 342 measurements (79.8%) and anti-DNase B titers were positive in 172 of 213 (80.8%). On the basis of their positive titers and clinical history, 345 children were deemed to meet criteria for PANDAS; per institutional policies, all 345 received prophylactic doses of benzathine benzylpenicillin monthly for at least five years. The prophylaxis effectively prevented <i>S. pyogenes</i> infections for all patients and 75% (n=258) were reported to have clinically significant improvement in their neuropsychiatric symptoms, usually within 3–5 months of initiating prophylaxis. Relapses were not uncommon, however, with 167 children in the combined sample of 371 PANDAS/PANS patients (45%) experiencing at least one neuropsychiatric exacerbation, usually concurrently with, or shortly after recovery from a nonspecific viral infection (<a class="bibr" href="#pandas.REF.lepri.2019.608" rid="pandas.REF.lepri.2019.608">Lepri, et al., 2019</a>).</p><p>These uncontrolled clinical observations confirm and extend the findings of two controlled trials of antibiotic prophylaxis which were conducted at NIMH by Garvey, et al., (<a class="bibr" href="#pandas.REF.garvey.1999.1564" rid="pandas.REF.garvey.1999.1564">Garvey, et al., 1999</a>) and Snider, et al. (<a class="bibr" href="#pandas.REF.snider.2002.331" rid="pandas.REF.snider.2002.331">Snider, et al., 2002</a>). Both studies were based on the hypothesis that neuropsychiatric symptom exacerbations in PANDAS can be prevented by effective prophylaxis against <i>S. pyogenes</i>; i.e., if you prevent <i>S. pyogenes</i>, you can prevent post-<i>S. pyogenes</i> sequelae, as has been shown in rheumatic carditis and Sydenham chorea (<a class="bibr" href="#pandas.REF.gerber.2009.1541" rid="pandas.REF.gerber.2009.1541">Gerber, et al., 2009</a>). The first NIMH investigation was an 8-month long, double-blind, balanced cross-over study (<a class="bibr" href="#pandas.REF.garvey.1999.1564" rid="pandas.REF.garvey.1999.1564">Garvey, et al., 1999</a>). Thirty-seven children who met the five classical criteria for PANDAS were randomized to receive either four months of the active compound (twice daily oral 250 mg penicillin V) followed by four months of a placebo (n=19), or a placebo (PLA) followed by penicillin (PCN) (n=18). Subjects were evaluated monthly for eight consecutive visits in order to assess severity of clinical symptoms (via ratings of tics, obsessive compulsive symptomatology, anxiety, depression, and overall severity) as well as undergo laboratory evaluation (including serum titers of antistreptolysin-O (ASLO), anti-deoxyribonuclease B (anti-DNaseB) and throat cultures). Adherence to the study design was incomplete, with 26 of the 37 (70%) children missing multiple doses of PCN or PLA during each phase. As a result, prophylaxis failed and there were no significant differences in the number of <i>S. pyogenes</i> infections occurring during PCN administration (14 <i>S. pyogenes</i>) or PLA (21 <i>S. pyogenes</i>); the infections were treated with off-study antibiotics and 18 children shared a total of 296 antibiotics days during the investigation (120 with PCN, 276 with PLA). Symptom exacerbations also occurred with similar frequency with active and placebo administration (35 during PCN phases, 38 with PLA). However, a parent global rating of symptom severity (a secondary outcome measure) did show significant differences with 22 of 27 sets of parents (81%) able to discern a difference between PLA and PCN administration and 18 of these choosing penicillin as the superior drug (% agreement = 0.82 and kappa = 0.61 – a significant difference). Some have speculated that these overall improvements were due to either an immunomodulatory or psychotropic effect of the penicillin, since these have been reported with beta-lactams and other antibiotics (<a class="bibr" href="#pandas.REF.obregon.2012.331" rid="pandas.REF.obregon.2012.331">Obregon, Parker-Athill, Tan, & Murphy, 2012</a>; <a class="bibr" href="#pandas.REF.tauber.2008.68" rid="pandas.REF.tauber.2008.68">Tauber & Nau, 2008</a>). However, given the study’s failure to achieve its primary aims, such speculations should be viewed with caution.</p><p>In a second NIMH prophylaxis trial, weekly diaries and a daily-dose delivery system were used to improve adherence in order to compare the effectiveness of azithromycin and penicillin prophylaxis in preventing neuropsychiatric symptom exacerbations (<a class="bibr" href="#pandas.REF.snider.2005.788" rid="pandas.REF.snider.2005.788">Snider, Lougee, Slattery, Grant, & Swedo, 2005</a>). Based on the results of the first prophylactic trial, penicillin was expected to serve as an “active placebo” and prevent only one-third of the <i>S. pyogenes</i> infections. The rate of streptococcal infections and symptom exacerbations from the year prior to study entry were determined by parental report and medical record review, and then compared to rates during the study year assessed with monthly clinical ratings and laboratory (ASLO and Anti-DNase B titers). Twenty-three (23) subjects were randomly assigned to prophylaxis with either penicillin V-K (250 mg/dose two times a day) or azithromycin (250 mg capsules two times a day on Day 1, 7, 14, etc., and matched placebo capsules two times a day on the intervening six days). Results showed a significant reduction (96%) of the rate of streptococcal infections with the penicillin group (n=11) decreasing from 1.9 (<u>+</u> 1.2SD) <i>S. pyogenes</i> infections and 2.1 (<u>+</u> 1.0) neuropsychiatric exacerbations in the year prior to study entry to 0.1 (<u>+</u> .3) <i>S. pyogenes</i> infections and 0.5 (<u>+</u> 0.5) exacerbations during the year of prophylaxis; azithromycin (n=12) showed a similar decrease: from 2.4 (<u>+</u> 1.1 SD) to 0.1 (<u>+</u>0.3) <i>S. pyogenes</i> infections and 1.8 (<u>+</u> 0.6) to 0.9 (<u>+</u> 0.5) neuropsychiatric relapses from baseline year to prophylactic year, respectively. <a class="figpopup" href="/books/NBK607260/figure/pandas.F9/?report=objectonly" target="object" rid-figpopup="figpandasF9" rid-ob="figobpandasF9">Figure 9</a> provides a graphic depiction of the differences in symptomatic months before and during antibiotic prophylaxis for ten of the subjects in the study.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpandasF9" co-legend-rid="figlgndpandasF9"><a href="/books/NBK607260/figure/pandas.F9/?report=objectonly" target="object" title="Figure 9. " class="img_link icnblk_img figpopup" rid-figpopup="figpandasF9" rid-ob="figobpandasF9"><img class="small-thumb" src="/books/NBK607260/bin/pandas-Image009.gif" src-large="/books/NBK607260/bin/pandas-Image009.jpg" alt="Figure 9. . Graphic depiction of the differences in symptomatic months before and during antibiotic prophylaxis for ten of the subjects in an antibiotic prophylaxis study in PANDAS." /></a><div class="icnblk_cntnt" id="figlgndpandasF9"><h4 id="pandas.F9"><a href="/books/NBK607260/figure/pandas.F9/?report=objectonly" target="object" rid-ob="figobpandasF9">Figure 9. </a></h4><p class="float-caption no_bottom_margin">Graphic depiction of the differences in symptomatic months before and during antibiotic prophylaxis for ten of the subjects in an antibiotic prophylaxis study in PANDAS. The left-hand column shows data from monthly symptom ratings for five patients randomized <a href="/books/NBK607260/figure/pandas.F9/?report=objectonly" target="object" rid-ob="figobpandasF9">(more...)</a></p></div></div><p>Taken together with the serologic data discussed above, the antibiotic trials provide compelling evidence of an etiologic role for <i>S. pyogenes</i> infections in acute-onset OCD/tics and other neuropsychiatric symptoms. Whether or not the pooled data are sufficient to justify treatment of PANDAS cases with antibiotics remains a matter of some debate, with the American Academy of Pediatrics Committee on Infectious Diseases issuing strong recommendations against antibiotics use (<a class="bibr" href="#pandas.REF241" rid="pandas.REF241">The Committee on Infectious Diseases, 2024</a>), and the U.S. PANS/PANDAS Clinical/Research Consortium concluding that there was sufficient research data and clinical experience (from more than 1,000 acute-onset patients treated at 17 different academic centers) to justify treatment with antibiotics for all acute-onset cases (PANS as well as PANDAS) (<a class="bibr" href="#pandas.REF.cooperstock.2017.594" rid="pandas.REF.cooperstock.2017.594">Cooperstock, Swedo, Pasternack, & Murphy, 2017</a>). Strong arguments can be made for both positions, and further research is needed to define the right approach. Until then, it seems prudent to follow the advice given by the NIMH investigators in the initial PANDAS publication from 1998, which is shown in <a class="figpopup" href="/books/NBK607260/figure/pandas.F10/?report=objectonly" target="object" rid-figpopup="figpandasF10" rid-ob="figobpandasF10">Figure 10</a>: “At initial presentation of a child with acute, dramatic onset of OCD and/or tics, obtain a throat swab (and if indicated a perianal swab) and culture for <i>S. pyogenes</i>—if positive, treat appropriately with antibiotics.”</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpandasF10" co-legend-rid="figlgndpandasF10"><a href="/books/NBK607260/figure/pandas.F10/?report=objectonly" target="object" title="Figure 10. " class="img_link icnblk_img figpopup" rid-figpopup="figpandasF10" rid-ob="figobpandasF10"><img class="small-thumb" src="/books/NBK607260/bin/pandas-Image010.gif" src-large="/books/NBK607260/bin/pandas-Image010.jpg" alt="Figure 10. . Impact of Antibiotic Treatment & Prophylaxis and Immunomodulatory Therapy in PANDAS." /></a><div class="icnblk_cntnt" id="figlgndpandasF10"><h4 id="pandas.F10"><a href="/books/NBK607260/figure/pandas.F10/?report=objectonly" target="object" rid-ob="figobpandasF10">Figure 10. </a></h4><p class="float-caption no_bottom_margin">Impact of Antibiotic Treatment & Prophylaxis and Immunomodulatory Therapy in PANDAS. Early intervention with antibiotics alleviates symptoms arising from an abnormal immune response triggered by group A streptococci (S. pyogenes). Failure to address <a href="/books/NBK607260/figure/pandas.F10/?report=objectonly" target="object" rid-ob="figobpandasF10">(more...)</a></p></div></div></div><div id="pandas.Acknowledgements"><h2 id="_pandas_Acknowledgements_">Acknowledgements</h2><p>The authors thank with much gratitude Dr Joseph J. Ferretti and Dr Vincent A. Fischetti for their critical review of the manuscript. We thank the chapter’s previous authors, Dr Graziella Orefici, Dr Francesco Cardona and Dr Carol Cox, all who made important contributions. SS was Director of Behavioral Pediatrics, National Institute of Mental Health (NIMH), Bethesda, MD. MWC was supported by grants from the National Institutes of Health(NIH) including R01HL35280, R01HL56267 and R01HL135165 from the National Heart Lung and Blood Institute(NHLBI), and was the recipient of an NHLBI MERIT Award R37HL35280; Intramural funding was through an NIMH supplement to MWC for R01HL56267, and PI of a T32 Immunology Training Grant AI007633 from the National Institute of Allergy and Infectious Diseases. CM was supported by grants from the Brain Foundation, PANDAS Network, Physicians PANDAS Network and was a T32 AI007633 National Institute of Allergy and Infectious Diseases Predoctoral and Postdoctoral Trainee. MWC serves as co-founder and chief scientific officer of Moleculera Labs at the University of Oklahoma Health Sciences Center Research Park in Oklahoma City, OK, USA. We express deepest gratitude to the Mara Family Office, Alberta, Canada who has supported our research and specifically our work herein through generous gifts each year for 10 years. Without their generosity and caring, our study could not have been accomplished. We express deep appreciation to the late Dr Michael Jenicke and the David Judah fund at the Department of Psychiatry, Harvard University, who provided support for our study of autoantibodies in a large group of PANDAS patients. We express deep gratitude for funding by the PANDAS Network, Pepsico Global Giving Fdn, the PANDAS Physicians Network (PPN), the late Brian Richmand and Autism Speaks for two Trailblazer Awards to MWC, and the Brain Foundation to MWC and CM. The views expressed in this article do not necessarily represent the views of the National Institute of Mental Health, National Heart Lung and Blood Institute or the National Institutes of Health, US Department of Health and Human Services, or US federal government.</p></div><div id="pandas.References"><h2 id="_pandas_References_">References</h2><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="pandas.REF.abdallah.2021.611036">Abdallah, A. M., & Abu-Madi, M. (2021, March
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The Journal of Experimental Medicine<em>,</em>
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210(3), 457-464.
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[<a href="/pmc/articles/PMC3600904/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3600904</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23420879" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23420879</span></a>]</div></p></li></ul></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK607260_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Susan Swedo</span>, MD<div class="affiliation small">Scientist Emerita, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.liamg@odewSnasuSrD" class="oemail">moc.liamg@odewSnasuSrD</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Chandra M. Menendez</span>, PhD<div class="affiliation small">Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Biomedical Research Center, Oklahoma City, OK 73104<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.cshuo@zednenem-ardnahc" class="oemail">ude.cshuo@zednenem-ardnahc</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Madeleine W. Cunningham</span>, PhD<div class="affiliation small">Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Biomedical Research Center, Oklahoma City, OK 73104<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.cshuo@mahgninnuc-enieledam" class="oemail">ude.cshuo@mahgninnuc-enieledam</a></div></div><div class="small">Corresponding author.</div></div><h3>Publication History</h3><p class="small">Created: <span itemprop="datePublished">July 7, 2024</span>; Last Update: <span itemprop="dateModified">September 13, 2024</span>.</p><h3>Copyright</h3><div><div class="half_rhythm">© The University of Oklahoma Health Sciences Center.<p class="small">Except where otherwise noted, this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC-BY-NC-ND 4.0). To view a copy of this license, visit <a href="http://creativecommons.org/licenses/by-nc-nd/4.0/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">http://creativecommons.org/licenses/by-nc-nd/4.0/</a>)</p></div></div><h3>Publisher</h3><p><a href="https://ouhsc.edu/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Oklahoma Health Sciences Center</a>, Oklahoma City (OK)</p><h3>NLM Citation</h3><p>Swedo S, Menendez CM, Cunningham MW. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) 2024 Jul 7 [Updated 2024 Sep 13]. In: Ferretti JJ, Stevens DL, Fischetti VA, editors. Streptococcus pyogenes: Basic Biology to Clinical Manifestations [Internet]. 2nd edition. Oklahoma City (OK): University of Oklahoma Health Sciences Center; 2022 Oct 8. Chapter 26.<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/spyogenes2/rheumaticfever/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/spyogenes2/glomer/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobpandasF1"><div id="pandas.F1" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%201.%20.%20MRI%20Brain%20Scan%20before%20and%20after%20treatment%20in%2014-year-old%20boy%20with%20PANDAS.&p=BOOKS&id=607260_pandas-Image001.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK607260/bin/pandas-Image001.jpg" alt="Figure 1. . MRI Brain Scan before and after treatment in 14-year-old boy with PANDAS." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 1. </span></h3><div class="caption"><p>MRI Brain Scan before and after treatment in 14-year-old boy with PANDAS. At symptomatic baseline (Before Treatment), head of caudate nucleus was 20% larger than expected for age, sex and weight. Following successful treatment with plasmapheresis, the caudate size had normalized (After Treatment) (<a class="bibr" href="#pandas.REF.giedd.1996.913" rid="pandas.REF.giedd.1996.913">Giedd, Rapoport, Leonard, Richter, & Swedo, 1996</a>).</p></div></div></article><article data-type="fig" id="figobpandasF2"><div id="pandas.F2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK607260/bin/pandas-Image002.jpg" alt="Figure 2. . Diagnostic criteria for PANDAS and PANS." /></div><h3><span class="label">Figure 2. </span></h3><div class="caption"><p>Diagnostic criteria for PANDAS and PANS. From (<a class="bibr" href="#pandas.REF.swedo.1998.264" rid="pandas.REF.swedo.1998.264">Swedo, et al., 1998</a>; <a class="bibr" href="#pandas.REF.swedo.2004.907" rid="pandas.REF.swedo.2004.907">Swedo, Leonard, & Rapoport, 2004</a>; <a class="bibr" href="#pandas.REF.swedo.2012.113" rid="pandas.REF.swedo.2012.113">Swedo, Leckman, & Rose, 2012</a>).</p></div></div></article><article data-type="fig" id="figobpandasF3"><div id="pandas.F3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK607260/bin/pandas-Image003.jpg" alt="Figure 3. . Sydenham’s chorea mAb 24." /></div><h3><span class="label">Figure 3. </span></h3><div class="caption"><p>Sydenham’s chorea mAb 24.3.1 induced increased levels of tyrosine hydroxylase in vivo. Chorea mAb 24.3.1 or isotype control were passively transferred into intracerebroventricular cannulated Lewis rats (Hilltop Lab Animals, Inc.) every day for five consecutive days. Brains were removed and formalin fixed. Comparative levels of tyrosine hydroxylase were assessed by immunohistochemistry on whole brain cross-sections. The sections were probed with a tyrosine hydroxylase-specific antibody (Pink), developed with Fast red substrate, and counterstained with hematoxylin (Blue). mAb 24.3.1 induced higher levels of tyrosine hydroxylase than the isotype control. <u>Tyrosine hydroxylase identifies the dopaminergic neurons in the Lewis rat brain tissue.</u> Elevated levels of tyrosine hydroxylase induced by chorea mAb 24.3.1 were seen in cortical neurons, but not in cerebellar neurons (inset). Taken from Kirvan, et al. (<a class="bibr" href="#pandas.REF.kirvan.2006a.173" rid="pandas.REF.kirvan.2006a.173">Kirvan, Swedo, Snider, & Cunningham, 2006a</a>).</p></div></div></article><article data-type="fig" id="figobpandasF4"><div id="pandas.F4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK607260/bin/pandas-Image004.jpg" alt="Figure 4. . Tritiated dopamine release by SKNSH human neuronal cells treated with (A) Sydenham’s chorea mAb 24." /></div><h3><span class="label">Figure 4. </span></h3><div class="caption"><p>Tritiated dopamine release by SKNSH human neuronal cells treated with (A) Sydenham’s chorea mAb 24.3.1, which induced a higher percentage release of 3H-dopamine from SK-N-SH cells than isotype control. SK-N-SH cells were plated at 1 X 106 cells/well. For radioactive dopamine uptake, cells were incubated with 3H-dopamine for 90 min in modified Kreb’s ringer buffer with 1 uM doperidone, 10uM nomifensine, 100nM nisoxetine, 100nM fluoxetine, 0.1mM ascorbic acid, 2mMCaCl2, 3mM KCl and 0.2mM MgCl2 under standard tissue culture conditions. Cells were then thoroughly washed and antibody was added to the wells. After a 30 min incubation, supernatants were collected and 3H-dopamine was measured by scintillation counting. Values were expressed as percentage of 3H-dopamine basal release. Statistical analysis performed by two-tailed t-test. (B) Sydenham’s chorea acute (A) sera induced significantly more 3H-dopamine release than matched convalescent (C) sera or pooled normal human sera (NHS). BSA, bovine serum albumin control. Taken from Kirvan, et al. (<a class="bibr" href="#pandas.REF.kirvan.2006a.173" rid="pandas.REF.kirvan.2006a.173">Kirvan, Swedo, Snider, & Cunningham, 2006a</a>).</p></div></div></article><article data-type="fig" id="figobpandasF5"><div id="pandas.F5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK607260/bin/pandas-Image005.jpg" alt="Figure 5. . Human Sydenham chorea 24." /></div><h3><span class="label">Figure 5. </span></h3><div class="caption"><p>Human Sydenham chorea 24.3.1 V gene expressed as a human V gene-mouse IgG1a constant region in Transgenic (Tg) mice targets dopaminergic neurons in the basal ganglia (most likely substantia nigra, based on location). Chimeric Tg24.3.1 VH IgG1a Ab expressed in Tg mouse sera penetrated dopaminergic neurons in Tg mouse brain in vivo. Colocalization of Tg 24.3.1 IgG1a (anti-IgG1a Ab, green Left Panel) and Tyrosine Hydroxylase Antibody (anti-TH Ab, yellow Middle Panel). TH is a marker for dopaminergic neurons. Left panel shows IgG1a (FITC labeled), center panel shows TH Ab (TRITC labeled), and right panel is merged image (FITC-TRITC). Brain sections (basal ganglia) of VH24.3.1 Tg mouse (original magnification 320), showing FITC labeled anti-mouse IgG1a (A), TRITC-labeled anti-TH Ab(B), and merged image (C). Controls treated with secondary antibody are negative. Figure is taken from (<a class="bibr" href="#pandas.REF.cox.2013.5524" rid="pandas.REF.cox.2013.5524">Cox, et al., 2013</a>).</p></div></div></article><article data-type="fig" id="figobpandasF6"><div id="pandas.F6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK607260/bin/pandas-Image006.jpg" alt="Figure 6. . Comparison of percent serum positive anti-neuronal autoantibody ELISA assays, antibody mediated CaMKII activation, and anti-streptolysin O assay results in PANDAS vs healthy subjects." /></div><h3><span class="label">Figure 6. </span></h3><div class="caption"><p>Comparison of percent serum positive anti-neuronal autoantibody ELISA assays, antibody mediated CaMKII activation, and anti-streptolysin O assay results in PANDAS vs healthy subjects. Taken from (<a class="bibr" href="#pandas.REF.chain.2020.564" rid="pandas.REF.chain.2020.564">Chain, et al., 2020</a>).</p></div></div></article><article data-type="fig" id="figobpandasF7"><div id="pandas.F7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK607260/bin/pandas-Image007.jpg" alt="Figure 7. . Autoantibody-mediated signaling in PANDAS, a basal ganglia encephalitis: Mechanisms for autoimmune movement and behavioral disorders." /></div><h3><span class="label">Figure 7. </span></h3><div class="caption"><p>Autoantibody-mediated signaling in PANDAS, a basal ganglia encephalitis: Mechanisms for autoimmune movement and behavioral disorders. In Sydenham’s chorea and PANDAS, neurons in the basal ganglia are attacked by autoantibodies against the group A carbohydrate epitope GlcNAc of Streptococcus pyogenes that react with neuronal receptors and antigens (<a class="bibr" href="#pandas.REF.kirvan.2003.914" rid="pandas.REF.kirvan.2003.914">Kirvan, Swedo, Heuser, & Cunningham, 2003</a>). This reaction activates signaling through the D1 and D2 dopamine receptors and CAMKII, which involves an increase in tyrosine hydroxylase, and dopamine release (<a class="figpopup" href="/books/NBK607260/figure/pandas.F4/?report=objectonly" target="object" rid-figpopup="figpandasF4" rid-ob="figobpandasF4">Figure 4</a>). D1R autoantibodies in neuropsychiatric sequelae that predominantly manifest as OCD and/or tics (PANDAS/PANS) activate D1R, increase intracellular cAMP and β-arrestin activity, and enhance the neurotransmission of dopamine to impact downstream signaling (Menendez, 2024). While D2R autoantibodies from SC decrease cAMP and increase dopamine release in which excess dopamine accumulation correlates with the choreiform movement phenotype in SC. Cases of PANDAS can exhibit OCD and neuropsychiatric symptoms mixed with choreatic movements. The pathogenesis derives from the hypothesis that elevated excess dopamine will affect the D1R more avidly in the presence of D1R autoantibodies, which sensitize the D1R to produce an exaggerated response to the excess dopamine and would lead to neuropsychiatric symptoms (Menendez, 2024). (Figure taken from Carapetis, Beaton, Cunningham, Guilherme, et al. (<a class="bibr" href="#pandas.REF.carapetis.2016.15084" rid="pandas.REF.carapetis.2016.15084">Carapetis, et al., 2016</a>).</p></div></div></article><article data-type="fig" id="figobpandasF8"><div id="pandas.F8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK607260/bin/pandas-Image008.jpg" alt="Figure 8. . Differences in Culture Technique by Blood Agar Plating of Group A Streptococci in Culture: Demonstrating the difficulties encountered when attempting to culture the throat or other samples from humans on a Blood Agar Plate." /></div><h3><span class="label">Figure 8. </span></h3><div class="caption"><p>Differences in Culture Technique by Blood Agar Plating of Group A Streptococci in Culture: Demonstrating the difficulties encountered when attempting to culture the throat or other samples from humans on a Blood Agar Plate. On the blood agar plate where the culture is streaked on the plate is not as clear for group A strep as the Blood Agar Pour Plates. A. 300 S. pyogenes colony-forming units (CFUs) were suspended in 5 mL Todd Hewitt broth in an 0.1mL plated (pour plate) in blood Columbia agar. The recovery was about 50%. B. 500 S. pyogenes CFUs put in 5 mL Todd Hewitt Broth. 0.1mL and 0.2 ml were pour plated in blood Columbia agar and compared to 0.1 mL directly streaked on the surface. The pour plates show the group A streptococcal beta hemolysis directly where it is not as clear on the culture streaked onto the blood agar plate. When a limited number of colonies are present, the point is that it may be difficult to identify them based on their beta hemolysis which is enhanced in a more anaerobic environment, hence, below or underneath in the agar enhances the production and visualization of the beta hemolysis whereas streaking on top of the blood agar plate does not.</p></div></div></article><article data-type="fig" id="figobpandasF9"><div id="pandas.F9" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK607260/bin/pandas-Image009.jpg" alt="Figure 9. . Graphic depiction of the differences in symptomatic months before and during antibiotic prophylaxis for ten of the subjects in an antibiotic prophylaxis study in PANDAS." /></div><h3><span class="label">Figure 9. </span></h3><div class="caption"><p>Graphic depiction of the differences in symptomatic months before and during antibiotic prophylaxis for ten of the subjects in an antibiotic prophylaxis study in PANDAS. The left-hand column shows data from monthly symptom ratings for five patients randomized to receive penicillin, while the right-hand column shows the same data for five patients randomized to receive azithromycin. There were no between-group differences in the study and the graphs are shown to demonstrate the symptomatic improvements occurring in response to antibiotic administration (months to the right of the red line). In all 10 patients, S. pyogenes infections were common in the year prior to entry into the antibiotics trial and absent during the blinded year of prophylaxis. Notice that children with more symptomatic months prior to study entry were less likely to achieve complete remission during prophylaxis. Data taken from Snider, et al. (<a class="bibr" href="#pandas.REF.snider.2005.788" rid="pandas.REF.snider.2005.788">Snider, Lougee, Slattery, Grant, & Swedo, 2005</a>).</p></div></div></article><article data-type="fig" id="figobpandasF10"><div id="pandas.F10" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK607260/bin/pandas-Image010.jpg" alt="Figure 10. . Impact of Antibiotic Treatment & Prophylaxis and Immunomodulatory Therapy in PANDAS." /></div><h3><span class="label">Figure 10. </span></h3><div class="caption"><p>Impact of Antibiotic Treatment & Prophylaxis and Immunomodulatory Therapy in PANDAS. Early intervention with antibiotics alleviates symptoms arising from an abnormal immune response triggered by group A streptococci (S. pyogenes). Failure to address S. pyogenes colonization may lead to inflammatory autoimmune basal ganglia encephalitis, particularly in individuals with complement C4 gene copy number alterations and deficiency, as identified by Frankovich, et al. (<a class="bibr" href="#pandas.REF.kalinowski.2023.315" rid="pandas.REF.kalinowski.2023.315">Kalinowski, et al., 2023</a>) potentially leading to more infections in PANDAS patients. Antibiotics serve as a crucial first-line preventive strategy, eliminating bacterial or streptococcal infections and improving or even curing PANDAS in early childhood. However, some individuals progress to episodic disease, requiring immunomodulatory therapies like intravenous immunoglobulin or plasmapheresis (<a class="bibr" href="#pandas.REF.frankovich.2017.574" rid="pandas.REF.frankovich.2017.574">Frankovich, et al., 2017</a>; <a class="bibr" href="#pandas.REF.latimer.2015.70" rid="pandas.REF.latimer.2015.70">Latimer, L'Etoile, Seidlitz, & Swedo, 2015</a>; <a class="bibr" href="#pandas.REF.perlmutter.1999.1153" rid="pandas.REF.perlmutter.1999.1153">Perlmutter, et al., 1999</a>). Antineuronal autoantibodies against the basal ganglia, can help identify basal ganglia encephalitis as demonstrated by Dale, et al., Brilot, et al., Cunningham, et al. laboratories, and our research (<a class="bibr" href="#pandas.REF.chain.2020.564" rid="pandas.REF.chain.2020.564">Chain, et al., 2020</a>; <a class="bibr" href="#pandas.REF.dai.2020.471" rid="pandas.REF.dai.2020.471">Dai, et al., 2020</a>; <a class="bibr" href="#pandas.REF.dale.2012.3453" rid="pandas.REF.dale.2012.3453">Dale, et al., 2012</a>; <a class="bibr" href="#pandas.REF.platt.2017.442" rid="pandas.REF.platt.2017.442">Platt, Agalliu, & Cutforth, 2017</a>; <a class="bibr" href="#pandas.REF.platt.2020.6708" rid="pandas.REF.platt.2020.6708">Platt, et al., 2020</a>) and underscores the condition's complexity. Both antibiotics and immunomodulatory therapies have shown success in managing PANDAS (<a class="bibr" href="#pandas.REF.frankovich.2017.574" rid="pandas.REF.frankovich.2017.574">Frankovich, et al., 2017</a>; <a class="bibr" href="#pandas.REF.latimer.2015.70" rid="pandas.REF.latimer.2015.70">Latimer, L'Etoile, Seidlitz, & Swedo, 2015</a>; <a class="bibr" href="#pandas.REF.perlmutter.1999.1153" rid="pandas.REF.perlmutter.1999.1153">Perlmutter, et al., 1999</a>). We refer readers to the position statement about autoimmune psychoses in The Lancet (<a class="bibr" href="#pandas.REF.pollak.2020.93" rid="pandas.REF.pollak.2020.93">Pollak, et al., 2020</a>) which defines dopamine receptor autoantibodies associated with Sydenham chorea and PANDAS (<a class="bibr" href="#pandas.REF.cox.2013.5524" rid="pandas.REF.cox.2013.5524">Cox, et al., 2013</a>; <a class="bibr" href="#pandas.REF.cunningham.2016.90" rid="pandas.REF.cunningham.2016.90">Cunningham & Cox, 2016</a>) in autoimmune psychoses.</p></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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