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Intravenous immunoglobulin (IVIG) is an intravenous administration of immunoglobulins (primarily IgG). The IVIG infusate is made by pooling immunoglobulins from thousands of human donors, thus increasing the diversity of the infusate. The mechanism of action of IVIG is unknown, as it has a wide range of effects, including local reactions with the host's immunoglobulins and systemic changes in the balance of cytokines and chemokines. Whether the concentration level of certain IgGs or subclasses of IgG is the therapeutic agent or whether the aggregate volume of immunoglobulin is the trigger, the therapy appears to "reset" the immune system and has proven effective for autoimmune disorders.

IVIG has been shown, in placebo-controlled trials, to significantly decrease (>60%) symptom severity and shorten the course of illness in PANDAS ( Perlmutter et al, Lancet 1999; KA Williams, SE Swedo, CA Farmer, et al. Journal of the American Academy of Child & Adolescent Psychiatry 2016). IVIG currently has FDA indications for the treatment of Kawasaki disease, idiopathic thrombocytopenic purpura (ITP), and other immune-mediated diseases of childhood.

In addition to the double-blind trial conducted at NIH, additional support for the benefits of IVIG are provided by a small number of published case reports and shared clinical experiences. These anecdotal reports showed that symptom improvements are comparable to those demonstrated in the placebo-controlled trial.

For most patients, a single course of IVIG is sufficient to produce significant improvements and, in some cases, complete remission of symptoms. Multiple monthly or quarterly infusions of IVIG for PANS/PANDAS have been recently studied with positive benefit for that cohort ( Melamed, Isaac et al. Journal of child and adolescent psychopharmacology vol. 31,2 (2021): 118-128). Research is ongoing as are current clinical trials.

Since IVIG is made from pooled human donor products, it carries inherent risk. This risk must be considered as part of the "risk-benefit" analysis whenever IVIG therapy is recommended. Chronic-static cases may require more aggressive and persistent immunomodulatory therapies. Patients that fall into the category should be referred to centers specializing in the treatment of neuroimmune disorders.

Symptom relief may occur as quickly as the first day or two following treatment, but is more commonly seen in 3 to 4 weeks, with some children seeing a delayed response occurring 8 to 12 weeks after infusion. Relief tends to be step-wise, with periods of improvement interspersed with periods of continuing symptoms; at first, the child might have a good hour or two, and then the periods of remission get longer until there are good days and bad days. In a minority of cases, the response of remission is as sudden and dramatic as the initial symptom onset. More often, it is a gradual process over a few weeks.

Unlike most medications whose ingredients and chemical compositions are carefully balanced so that every pill or unit is the same, IVIG consists of IgG antibodies captured from donors at donation sites across the US and the world. Each IVIG batch therefore consists of different concentrations of IgG-specific antibodies. For example, batch #1 may have IgG-specific antibodies to pathogen A, while batch #2 may have none. Therefore, the 10%-15% failure rate reported by clinicians is not unexpected. Failures of IVIG therapy also have been reported to occur when patients were suffering from an infection at the time the infusion of IVIG was given. Thus, it is important to ensure that children are free of strep infections and any other bacterial or viral infections at the time of the IVIG infusion. A short course of antibiotics might be used to clear occult infections. Additionally, early failures may occur after treatment when children are exposed to strep infections, as the exposure (even without an infection) produces an immune response. Clinicians and parents will need to work together to reduce exposure risk by instituting good hygiene practices in the home, avoiding crowded situations (like shopping malls, amusement parks, etc.), and isolating sick siblings away from the child with PANS/PANDAS. Some children have benefited from "strep surveillance" in their schools, wherein the school nurse monitors illness-related absences and notifies the child's parents when a classmate or other close acquaintance has had a strep infection. Antibiotic prophylaxis should always accompany IVIG therapy. For further discussion, see the Antibiotic section of Treatment Options. Should a failure occur due to an infection acquired shortly after IVIG treatment, another round of IVIG might be considered once the infectious agent or infection is cleared.

While patients will suffer relapses as previously discussed, they most often are not experiencing the level of anxiety or the intensity of the symptoms seen prior to IVIG treatment. Age and length of time from onset to treatment may affect the time of recovery and impact of IVIG, although patients of all ages and years of suffering have been successfully treated. Many of the original patients of are now 15 to 20 years older and are healthy. Others have also remained symptom-free, although when infected with a pathogen, especially Group A strep, must use antibiotics to control the flare-up periods.

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Intravenous immunoglobulin (IVIG) is an intravenous administration of immunoglobulins (primarily IgG). The IVIG infusate is made by pooling immunoglobulins from thousands of human donors, thus increasing the diversity of the infusate. The mechanism of action of IVIG is unknown, as it has a wide range of effects, including local reactions with the host's immunoglobulins and systemic changes in the balance of cytokines and chemokines.

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PANS/PANDAS material for download and printing.

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Table and Text Excerpt from: "Treatment of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS)"
SE Swedo (NIMH), J Frankovich (Stanford), TK Murphy (Univ S Florida)
In press, Journal of Child & Adolescent Psychopharmacology

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Table and Text Excerpt from: "Treatment of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS)" SE Swedo (NIMH), J Frankovich (Stanford), TK Murphy (Univ S Florida) In press, Journal of Child & Adolescent Psychopharmacology

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When Heather Korbmacher's 10-year-old son began having extreme emotional responses to otherwise normal situations, she began to wonder what was happening to her child. When these responses erupted into violent rages, severe panic attacks, debilitating anxiety and phobias, an inability to eat, and a rigid need for everything to be just right, this mother knew something was profoundly wrong.

In this true story, one mother shares her journey to find healing for her son and her family. She unpacks the terrifying heartache of suddenly losing the son she once knew, the fierce battle that a parent endures to save a child, and the peace of finding health and a new normal.

You will be moved by the courage of Heather's determination to find answers, save her son, and take back control of her life. You will find hope and guidance as you read this account of one family's quest for healing. You will be inspired to fight your own battles, knock down barriers, and ultimately find your own peace.

Heather Korbmacher is a dedicated mother and fierce advocate for families living with PANDAS/PANS/AE. She resides in Bellingham, WA with her loving husband and two tenacious children. Connect with her at CourageousParent.com

A portion of the proceeds will go to support PANDAS Network, dedicated to improving diagnosis and treatment of children with PANDAS/PANS/AE.

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What Happened to My Child?: A Mother's Courageous Journey to Save Her Son

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What Happened to My Child?: A Mother's Courageous Journey to Save Her Son [Korbmacher, Heather Rain Mazen, Diana, Pohlman, Carla, Atherton] on Amazon.com. *FREE* shipping on qualifying offers. What Happened to My Child?: A Mother's Courageous Journey to Save Her Son

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PANS & PANDAS: $1.5M Grant Appropriation in the NC State Budget

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"His abrupt transformation is a classic presentation of this hideous disease."

Brian Barnes is a father living in suburban Minnesota with his wife Natalie Barnes and their four children. Their oldest son Parker was just 10 years old when the Barnes family says he went from being a rambunctious and outgoing boy to having odd tics and strange moodiness in April 2017. For months, the Barnes say, Parker had seizures and was dealing with debilitating anxiety, rage and depression. An emergency room doctor recommended that Parker be evaluated by a psychiatrist. As Parker was evaluated, one doctor became struck by one factor in his case. She learned that Parker's symptoms had first begun months earlier, when he had been diagnosed with strep throat, and said he might have something called Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). Brian and Natalie Barnes took Parker to more than a dozen doctors in Minnesota looking for a remedy for PANDAS, showing them home videos of his erratic behavior. They got limited results. A pediatric neurologist they saw confirmed Parker's PANDAS diagnosis after evaluating him for two hours.
Our son Parker was a wonderful 10-year-old boy.

As the eldest of our four kids, he was a most capable young man. He got good grades in school, was popular among his classmates, adored by his teachers and loved by his family. We nicknamed him "The Lead Dog" as in how a dog team is directed by a natural leader at the head of the team.

He was organized, stone reliable and obviously smart with a dry sense of humor and a wry smile that gave the impression of an old soul. His reliability was way above his peers. You could count on him every time you needed him.

Somewhere in the night Parker's immune system responded to a typical infection and quietly began a dysfunctional campaign against his brain. In a matter of months he had descended into psychosis, hallucinations, suicidal actions, rages, torturous anxiety, obsessive behavior, compulsions and seizures. He experienced a loss of his fine motor skills and a loss of appetite. He lost weight and eventually lost the ability to speak for more than four months.

After repeated evaluations from multiple medical specialists along with exhaustive research and data collection from every possible angle, we were left with a diagnosis of a little-known condition called Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) or sometimes called Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). Because Parker was 10 years old and we had a decade of rock-solid experience with his personality and character, his abrupt transformation is a classic presentation of this hideous disease.

Oftentimes for days on end he would be reduced to a crying ball in a corner of his room, unable to speak, interact or function. Huge tears would flow down his cheeks for hours, day after day, as he cried out in his mental agony. It is a nightmare the likes of which we never knew existed. Our lives were turned upside down in an instant and everything we knew had changed. We battled disbelief, confusion, disinformation and finally the realization that this monster had consumed our boy and that we were in for the fight of our lives.

I used to think that the medical system was by design steadfast and determined to find a cure for whatever ails you, and certainly for whatever ails your child. To my surprise, I found that we were expected to be the number-one care coordinator and researcher for our son's condition. In fact, many in the medical community flatly turned a blind eye, alluded that we were making it up or incorrectly diagnosed our son with a psychiatric disorder. We were later warned that psychiatric drugs will typically make it worse.

Our insurance company did not want to pay for treatment even after a correct diagnosis. We were forced to fight with uninformed doctors, tight-fisted insurance companies and disbelieving but well-intentioned family and friends, all while caring for our disintegrating child.

To compound matters, there is a small group of vocal doctors that, for their own reasons, stubbornly lead the opposition to this disease on the national stage and seemingly have a stranglehold on the progression of treatment. They dispute the science and ignore successful treatments.

Our story is not unique, but frighteningly common. When children begin demonstrating the rapid dysfunctional symptoms of PANDAS/PANS, the kids suffer terribly and as a result the parents are driven insane trying to battle the onslaught of symptoms. To say that it's maddening would be a huge understatement.

We are here. Our kids are here. We need help and it can be a lonely battle. The worst part is that there may be a one in 200 chance that it will happen to your child or a child you know.

Listen.
Watch Brian Barnes and his son Parker's story on ABC News' "20/20" FRIDAY at 10 p.m. ET and "Nightline" at 12:35 a.m. ET. The opinions expressed by the author do not necessarily reflect those of ABC News.

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COLUMN: 'This monster had consumed my boy': What life is like when your child is diagnosed with PANDAS

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"His abrupt transformation is a classic presentation of this hideous disease." Brian Barnes is a father living in suburban Minnesota with his wife Natalie Barnes and their four children. Their oldest son Parker was just 10 years old when the Barnes family says he went from being a rambunctious and outgoing boy to having odd tics and strange moodiness in April 2017.

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A dedicated group of parents, clinicians, scientists and business leaders in greater Boston, Massachusetts, is guiding the Mending Minds Foundation (MMF) to partner with world-class scientists in the hub of international research and discovery. Our goal is to support excellence in clinical care while providing sustainable funding of cutting-edge science to build the groundwork for understanding of PANDAS and other childhood post-infectious neuroimmune disorders.

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The American Psychiatric Association (APA) has updated its Privacy Policy and Terms of Use, including with new information specifically addressed to individuals in the European Economic Area. As described in the Privacy Policy and Terms of Use, this website utilizes cookies, including for the purpose of offering an optimal online experience and services tailored to your preferences.

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Moleculera Labs - PANS/PANDAS: 2 children's stories | Facebook

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Effects of PANS/PANDAS on Communication: A Review of the Literature and Implications for the SLP

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PANS, or Pediatric Acute Onset Neuropsychiatric Syndrome, is characterized by a dramatic onset of neuropsychiatric symptoms such as obsessions, compulsions, tics, depression and anxiety. This syndrome is typically triggered by infections, metabolic disturbances or other inflammatory reactions. PANS…

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PANS/PANDAS Information and Video – Dearborn Academy

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Margaret (Peggy) Chapman, CNS-BC, medical advisor to the New England PANS/PANDAS Association (NEPANS)

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Federica Murgia 1†, Antonella Gagliano 2,3*†,

Marcello G. Tanca ²,

Noga Or-Geva ⁴, Aran Hendren 1,5,

Sara Carucci 2,3,

Manuela Pintor ³, Francesca Cera ², Fausto Cossu ⁶,

Stefano Sotgiu ⁷, Luigi Atzori 1† and

Alessandro Zuddas 2,3†

Clinical Metabolomics Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

Child and Adolescent Neuropsychiatry Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

Child and Adolescent Neuropsychiatry Unit, "A. Cao" Peditric Hosptal, "G. Brotzu" Hospital Trust, Cagliari, Italy

Interdepartmental Program in Immunology, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States

Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom

Paediatric Clinic, "A. Cao" Hospital, Cagliari, Italy

Child Neuropsychiatry Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy

Introduction: PANS is a controversial clinical entity, consisting of a complex constellation of psychiatric symptoms, adventitious changes, and expression of various serological alterations, likely sustained by an autoimmune/inflammatory disease. Detection of novel biomarkers of PANS is highly desirable for both diagnostic and therapeutic management of affected patients. Analysis of metabolites has proven useful in detecting biomarkers for other neuroimmune-psychiatric diseases. Here, we utilize the metabolomics approach to determine whether it is possible to define a specific metabolic pattern in patients affected by PANS compared to healthy subjects.

Design: This observational case-control study tested consecutive patients referred for PANS between June 2019 to May 2020. A PANS diagnosis was confirmed according to the PANS working criteria (National Institute of Mental Health [NIMH], 2010). Healthy age and sex-matched subjects were recruited as controls.

Methods: Thirty-four outpatients referred for PANS (mean age 9.5 years; SD 2.9, 71% male) and 25 neurotypical subjects matched for age and gender, were subjected to metabolite analysis. Serum samples were obtained from each participant and were analyzed using Nuclear Magnetic Resonance (NMR) spectroscopy. Subsequently, multivariate and univariate statistical analyses and Receiver Operator Curves (ROC) were performed.

Results: Separation of the samples, in line with the presence of PANS diagnosis, was observed by applying a supervised model (R ²X = 0.44, R ²Y = 0.54, Q ² = 0.44, p-value < 0.0001). The significantly altered variables were 2-Hydroxybutyrate, glycine, glutamine, histidine, tryptophan. Pathway analysis indicated that phenylalanine, tyrosine, and tryptophan metabolism, as well as glutamine and glutamate metabolism, exhibited the largest deviations from neurotypical controls.

Conclusion: We found a unique plasma metabolic profile in PANS patients, significantly differing from that of healthy children, that suggests the involvement of specific patterns of neurotransmission (tryptophan, glycine, histamine/histidine) as well as a more general state of neuroinflammation and oxidative stress (glutamine, 2-Hydroxybutyrate, and tryptophan-kynurenine pathway) in the disorder. This metabolomics study offers new insights into biological mechanisms underpinning the disorder and supports research of other potential biomarkers implicated in PANS.

Introduction

Pediatric acute-onset neuropsychiatric syndrome (PANS) is a clinically heterogeneous disorder first described in 2012 after the modification of the Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) criteria ( Swedo et al., 1998). The major clinical features of PANS consist of an acute-onset obsessive-compulsive disorder and/or severe eating restrictions, with at least two concomitant cognitive, behavioral, or affective symptoms such as anxiety, irritability, or depression ( Swedo et al., 2012; Frankovich et al., 2015). These children experience neuropsychiatric symptoms in temporal association not only with GAS infection, but also with exposure to a wide variety of other infections and environmental or metabolic changes; thusly, the PANDAS diagnosis fell under the newly established umbrella category PANS ( Swedo et al., 2012). The gender ratio is around 2:1, and symptoms usually commence in early childhood (7.3 ± 2.7 years). Clinical presentations were similar across sites, with all children presenting with acute-onset OCD symptoms and a constellation of other symptoms and disorders, including separation anxiety (86-92%), school issues (75-81%), sleep disruptions (71%), tics (60-65%), urinary symptoms (42-81%), and others ( Swedo et al., 2015). As is the case with PANDAS, PANS is thought to be sustained by immune-mediated mechanisms ( Swedo et al., 2015; Spinello et al., 2016), specifically those of so-called molecular mimicry occurring when pathogenic microorganisms express an antigenic structure indistinguishable (in terms of the amino acid sequence or three-dimensional structure) from self-antigens.

Under this rationale, the initiation of the symptomatic state results from an event (e.g., Group A Streptococcal infection) causing a localized immune response in the central nervous system (CNS), and the chronic relapsing course is due to the persistence of the immunological imbalance even after the resolution of the acute phase of the infection ( Swedo et al., 2015). In PANS, various aetiological agents, including viruses ( Hoekstra et al., 2005), Mycoplasma pneumonia ( Müller et al., 2004), and Haemophilus influenza, supposedly act as triggers for activation of the immune response, together with the consequent release of chemical mediators of inflammation at the CNS level ( Swedo et al., 2012; Frankovich et al., 2015). Structural and Functional abnormalities of the cortico-basal ganglia circuitry, similar to that seen in those with acute Sydenham's Chorea, have been described in PANDAS. In particular, an enlarged striatal volume ( Giedd et al., 2000; Elia et al., 2005) and an inflammatory state of the striatum, confirmed by positron emission tomography using a marker of microglial activation ( Kumar et al., 2015), has been reported in PANDAS. A recent diffusion-weighted magnetic resonance imaging study identified cerebral microstructural differences in children with PANS in multiple brain structures (including deep gray matter structures such as the thalamus, basal ganglia, and amygdala) putatively related to a neuroinflammatory state ( Zheng et al., 2020). In cohorts of rigorously selected subjects with PANS, evidence of post-infectious autoimmune processes and/or a condition of neuroinflammation was observed in over 80% of cases ( Swedo et al., 2017).

A very recent paper showed that antibodies from children with PANDAS bind specifically to striatal cholinergic interneurons and alter their activity, sustaining the pathophysiology of rapid-onset obsessive-compulsive symptoms ( Xu et al., 2021). Treatment of PANS involves different approaches: antibiotics to remove the potential source of neuroinflammation, anti-inflammatory and immunomodulatory treatments to regulate the immune system, and psychiatric medications to provide symptomatic relief ( Swedo et al., 2015).

Despite this accumulating evidence, PANS is still regarded as a controversial clinical entity, consisting of a complex combination of psychiatric symptoms and adventitious changes and the expression of various serological variables of an autoimmune/inflammatory disease ( Gagliano et al., 2020). In this scenario, research for new specific biomarkers is strongly desirable.

Metabolomics allows the simultaneous and relative quantification of various metabolites within a given biological sample ( Mamas et al., 2011) through the application of two sensitive and specific methodologies, Nuclear Magnetic Resonance (NMR) ( Smolinska et al., 2012) and Mass Spectrometry (MS) ( Dettmer et al., 2007). By systematically identifying and quantifying the small molecule profile of a tissue or biofluid sample, known as "the metabolome," metabolomics is thought to directly reflect the biochemical activity in a given organism or biological sample at a specific point in time. In the last decade, attempts have been made to use metabolomics to identify biomarkers of the various CNS disorders ( Quinones and Kaddurah-Daouk, 2009; Hatano et al., 2016; Murgia et al., 2017; Pedrini et al., 2019); for example levels of taurine, succinate and other molecules like glycine and β-alanine were elevated in autistic subjects compared to controls ( Glinton and Elsea, 2019). Currently, there are no systematic metabolomics datasets for PANS patients. A single case-study of a 10-year-old girl with PANS showed several metabolic pathways related to dysbiosis of microbial activity, protein biosynthesis, and amino acid metabolism ( Piras et al., 2020).

The present study aims to identify specific serum metabolomic profiles in a sample of children clinically diagnosed with PANS, measured through ¹ H-NMR spectroscopy.

Materials and Methods

Study Population and Inclusion Criteria

PANS patients referred to the outpatient clinics of Child and Adolescent Neuropsychiatric Unit "G. Brotz" Hospital Trust, Cagliari (June 2019 to May 2020), were enrolled in this observational study.

An extensive physical, neurological, and psychiatric examination was performed. Moreover, a clinical laboratory test, consisting of a complete blood count, renal and liver function tests, mineral panel, thyroid indices, and inflammation blood markers, was undertaken to exclude metabolic concomitants or systemic diseases. All participants were assessed by a panel of standardized scales and questionnaires encompassing the Pediatric Acute Neuropsychiatric Symptom Scale (PANSS) ( Pandas Network, 2018) to screen the symptoms and their severity. Details of the PANSS scale are reported in Supplementary Materials.

Diagnosis of PANS was confirmed by two child psychiatrists (AG and FC), according to the PANS working criteria defined by experts convened at the National Institute of Mental Health (NIH) in July 2010 ( Swedo et al., 2012):

(I) Abrupt dramatic onset of OCD or severely restricted food intake;

(II) Concurrent presence of additional neuropsychiatric symptoms (with similarly severe and acute onset), from at least two of the following seven categories:

(1) Anxiety;

(2) Emotional lability and/or depression;

(3) Irritability, aggression, and/or severely oppositional behaviors;

(4) Behavioral (developmental) regression;

(5) Deterioration in school performance (related to attention-deficit/hyperactivity disorder [ADHD]-like symptoms, memory deficits, and cognitive changes);

(6) Sensory or motor abnormalities;

(7) Somatic signs and symptoms, including sleep disturbances, enuresis, or urinary frequency;

(III) Symptoms not better explained by a known neurological or medical disorder, such as Sydenham's Chorea.

Exclusion criteria were the following: (I) occurrence of immunological diseases or cancer; (II) presence of other medical or neurological/psychiatric diseases; (III) active treatment with psychoactive substances, non-steroidal anti-inflammatory drugs or corticosteroid agents; (IV) patients' unwillingness to participate in the study.

Among a total of 52 consecutive outpatients referred for PANS, 34 met the inclusion criteria of this study. The mean age at recruitment was 9.5 years. (SD 2.9); the gender ratio was 10/24 (71% male). The serum samples of the affected patients were compared to the serum of 25 neurotypical subjects matched for age and gender (mean age 12.12 years.; SD 2.1, 64% male), and living in the same geographic area as the clinical group. The control group encompassed children with no autoimmune pathologies, neurodevelopmental and psychiatric disorders and with adequate academic achievement and functional performance. The aim of the study was to compare the metabolic profile of the two classes of patients, considering both a model including all of the samples together and models considering males and females separately, to underline possible differences based on gender.

The study was conducted with the approval of the independent Ethical Committee of Cagliari University Hospital (Prot. PG/2019/7413 on 29/05/2019). All the parents and all children older than 12 were given a full explanation of the study's method and purpose. The parents signed the consent form, agreeing to participate, and to the data being published. Furthermore, the research was conducted in accordance with the Declaration of Helsinki, V edition (2000).

Sample Preparation for ¹H-NMR

Ten milliliter of blood were collected from each subject and were centrifuged at 2,500 g for 10 min at 4°C. The obtained serum samples were stored at −80°C until analysis. Subsequently, samples were thawed and treated with a modified Folch method ( Bligh and Dyer, 1959; Lorefice et al., 2019) to extract and separate hydrophilic and lipophilic metabolites. 400 μL of each serum sample were mixed with 600 μL of methanol, 600 μL of chloroform, and 175 μL of Milli-Q water. The samples were vortexed for 1 min and centrifuged for 30 min at 1700 g at room temperature. Aliquots (10 μL) from each sample were used to create a pool for quality control (QC) samples. The QC samples were analyzed at the beginning and the end of the analysis. The hydrophilic and hydrophobic phases were obtained. The water-phase was divided into two aliquots and concentrated overnight using a speed vacuum centrifuge.

¹H-NMR Analysis

For the ¹H-NMR analysis, 700 μL of the water-phase containing low-weight molecules (amino acids, sugars, etc.) for each sample were concentrated overnight in a speed-vacuum. The concentrated water-phase was resuspended in 690 μL of D ₂ O phosphate buffer (pH 7.4) and 10 μL trimethylsilyl propanoic acid (TSP) 5.07 mM. TSP was added to provide an internal reference for the chemical shifts (0 ppm). A total of 650 μL of the solution was transferred to a 5 mm NMR tube.

The samples were analyzed with a Varian UNITY INOVA 500 spectrometer (Agilent Technologies, Inc., Santa Clara, CA, United States), which was operated at 499 MHz and equipped with a 5 mm triple resonance probe with z-axis pulsed field gradients and an auto-sampler with 50 locations. One-dimensional ¹H-NMR spectra were collected at 300 K with a pre-sat pulse sequence to suppress the residual water's signal. The spectra were recorded with a spectral width of 6,000 Hz; a frequency of 2 Hz; an acquisition time of 1.5 s; a relaxation delay of 2 ms; and a 90° pulse of 9.5 μs. The number of scans was 256. Each Free Induction Decay (FID) was zero-filled to 64 k points and multiplied by a 0.5 Hz exponential line broadening function. The spectra were manually phased and baseline corrected. Using MestReNova software (version 8.1, Mestrelab Research SL), each ¹ H-NMR spectrum was divided into consecutive "bins" of 0.04 ppm. The spectral area investigated was the region between 0.6 and 8.6 ppm. The regions between 4.60 and 5.2 ppm and between 5.24 and 6.6 ppm were excluded to remove variations in the pre-saturation of the residual water resonance and spectral regions of noise. To minimize adverse effects resulting from the serum samples' differing concentrations, the integrated area within each bin was normalized to a constant sum of 100. The final data set consisted of a 150 × 59 matrix. The columns represent the normalized area of each bin (variables), and the rows represent the samples (subjects).

Multivariate Statistical Analysis

Multivariate statistical analysis was performed on ¹H-NMR data with SIMCA-P software (ver.15.0, Sartorius Stedim Biotech, Umea, Sweden; ( Eriksson et al., 2013). The variables were Pareto scaled to emphasize all metabolite signals and reduce the spectral noise for the ¹ H-NMR analysis.

The initial data analyses were conducted using Principal Component Analysis (PCA), which is used to explore the sample distributions without classification. In particular, PCA analysis was performed to observe intrinsic clusters and find outliers. For this aim, the DmodX and Hotelling's T2 tests were applied. The PCA model was performed including the QC samples to corroborate the quality of the analysis.

Orthogonal Partial Least Square Discriminant Analysis (OPLS-DA) was subsequently applied. OPLS-DA maximizes the discrimination between samples assigned to different classes, in this case discriminating between patients with PANS and healthy subjects. OPLS-DA was also used to perform a gender analysis. In particular, pathological male and female subjects were separately compared to the matched controls. The aim of this analysis was to find specific metabolic features to define gender-related differences in the PANS profile which could have influenced the final result. The OPLS-DA model removes variability not relevant to class separation ( Rousseau et al., 2008). The variance and the predictive ability (R ²X, R ²Y, Q ²) were established to evaluate the suitability of the models. An additional permutation test ( n = 400) was performed to validate the model. This rigorous test compares the fit of the original model with that of randomly permuted models ( Lindgren et al., 1996). In particular, the permutation test evaluates model validity in terms of the explained variance parameter (R ²) and the cross-validation parameter (Q ²), that indicates fit and accuracy of the prediction, respectively. A CV-ANOVA (analysis of variance testing of cross-validated predictive residuals) test was performed simultaneously to establish the significance of the OPLS-DA model ( p < 0.05). Through the multivariate analysis it was also possible to investigate a potential linear relationship between the metabolic profile (predictor variables, e.g., metabolites) and the clinical parameters such as dependent variables like age and scale of severity for PANS. For this aim, PLS projection to latent structure regression models were performed.

Variables corresponding to a VIP (Variables Important in the Projection) value of > 1 (a measure of their relative influence on the model) from the OPLS-DA model, together with the relative S-plot, were selected as the most important. Indeed, VIPs of > 1 are the most relevant for explaining Y (assignment of two classes). The selected variables were identified using the Chenomx NMR Suite 7.1 (Chenomx Inc., Edmonton, Alberta, Canada; Weljie et al., 2006). GraphPad Prism software (version 7.0, GraphPad Software, Inc., San Diego, CA, United States) was used to perform the univariate statistical analysis of the data. To verify the significance of the metabolites resulting from multivariate statistical analysis, the U-Mann Whitney test was performed, followed by ROC curves to test the sensitivity and specificity of the metabolites with p-values < 0.05. ROC curves are conventionally used to evaluate diagnostic performance in clinical research. Moreover, Pearson correlation between the clinical parameters (age and PANSS scale) was performed for each significant metabolite.

Pathway Analysis

To help researchers identify the most relevant pathways involved in the conditions under study, metabolic pathways were generated using MetaboAnalyst 5.0 ( Chong et al., 2019), a web server designed to obtain metabolomic data analysis, visualization, and biological interpretation. In particular, the pathway analysis module of MetaboAnalyst 5.0 helps researchers identify the most relevant pathways involved in the conditions under study using the high-quality Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways as the backend knowledgebase. The Pathway Analysis module combines results from powerful pathway enrichment analysis with pathway topology analysis.

Results

The Metabolic Signature of PANS Patients Is Distinct From Healthy Controls

Utilizing ¹H-NMR analysis of serum samples, we identified a total of 44 hydrophilic metabolites ( Supplementary Figure 1). Each of these metabolites, which were quantified for each patient, were organized in a matrix to undergo multivariate analysis. Firstly, non-supervised multivariate Principal Component Analysis (PCA) was performed using the bins dataset. The aim of this approach was to identify any outlying samples or any possible sample cluster without previous classification. The obtained score plot and the result of the Hotelling's T ² test did not identify any outliers (data not shown). A separation of the samples, in line with the presence of PANS diagnosis, was subsequently observed after applying the supervised OPLS-DA model ( Figure 1A). These results were then validated using the respective permutation test ( Figure 1B). The statistical parameters of the model were: R ²X = 0.44, R ²Y = 0.57, Q ² = 0.44, p < 0.0001. The cumulative values of total Y-explained variance (R ²) and the Y-predictable variation (Q ²) values of the permutation test indicated proper modeling (Intercept R ²\Q ² = 0.17/−0.28). The same patient classification was used to construct the supervised model considering males and females separately ( Supplementary Figure 2). The aim of this analysis was to define possible gender differentials in metabolite concentrations which could have influenced the result. A good separation was also observed in these models, and we further observed that the metabolites responsible for the separation were the same as those causing separation in the complete model. Moreover, demographic data such as age, and the phenotypic severity were correlated with the total metabolic profile. A weak correlation was found between age and the metabolic profile (R ² was equal to 0.52) while a strong correlation was found between the phenotypic severity parameters express as PANSS scale evaluation and the metabolic profile (R ² was equal to 0.7). The results are shown in Figures 2A,B.

Figure 1. Comparison between PANS and Controls patients. (A,B) OPLS-DA models of the analyzed classes. PANS (white circles) vs. Controls subjects (black boxes) with the respective permutation test. (C) Bar graphs and (D) ROC curves of the metabolites exhibiting a p-value of < 0.05. U-Mann Whitney analysis was used, and subsequently Holm-Bonferroni correction was applied. White bars represent the PANS class while black bars represent the control patients. * p < 0.05.

Figure 2. (A) PLS correlation analysis between the metabolic profile of the enrolled subjects and the age. (B) PLS correlation analysis between the metabolic profile of the affected patients and the PANSS severity score.

Metabolite Analysis Highlights Energy and Neurotransmission Pathways, Corresponding to the Clinical Symptomology of PANS

Subsequently, the most significant variables were identified through analysis of the S-plot and through the corresponding VIP-value of the complete supervised model. Variables with a VIP-value of > 1 were identified with Chenomx and underwent univariate statistical analysis with the U-Mann Whitney test. A subsequent Holm-Bonferroni correction for multiple comparisons was applied.

2-Hydroxybutyrate and glycerol were found to be increased in PANS patients, while asparagine, glycine, glutamine, histidine, tryptophan, tyrosine were found to be decreased. These metabolites exhibited the most significant differences between PANS and Controls, denoted by a p-value of < 0.05 corrected for multiple comparisons (Holm-Bonferroni test, Figure 1C), and were selected to create ROC curves ( Figure 1D); the corresponding statistical parameters are reported in Table 1. Considering the result of the PLS correlation analysis, we decided to test the correlation between the PANSS scale and each significantly altered metabolite in the PANS class compared to the control subjects by conducting Pearson correlation analysis. Only glycine ( p = 0.03), tryptophan ( p = 0.02) and tyrosine ( p = 0.01) were found to be significantly correlated with the severity of the syndrome ( Figure 3).

Table 1. Statistical parameters of the univariate analysis from the comparisons between PANS and Controls.

Figure 3. Pearson correlation analysis between the concentrations of the significant metabolites and the PANSS severity score. Only glycine, tryptophan and tyrosine showed a significant correlation with the clinical parameter considered.

Pathway Enrichment Indicates the Involvement of Inflammatory and Neurotransmitter Pathways in PANS

The discriminant metabolites of the comparison between PANS and controls which passed the Holm-Bonferroni correction (2-hydroxybutyrate, asparagine, glutamine, glycerol, glycine, histidine, tryptophan, and tyrosine) were used to perform the pathways analysis and the enrichment analysis. MetaboAnalyst was used to characterize the altered pathways in the PANS group. Compared to Controls, the most altered pathways that we considered for the interpretation of the data were histidine metabolism, phenylalanine, tyrosine and tryptophan metabolism, glutathione metabolism, glycine, serine and threonine metabolism, alanine, aspartate and glutamate metabolism, glutamine, and glutamate metabolism, according to the parameters suggested by the software including pathway impact and p-value ( Figure 4).

Figure 4. The metabolic pathways most altered in patients with PANS diagnosis were histidine metabolism, phenylalanine, tyrosine and tryptophan metabolism, tyrosine metabolism, glutathione metabolism, glycine, serine and threonine metabolism, alanine, aspartate and glutamate metabolism, glutamine and glutamate metabolism. (A) The size of the circles represent the pathway impact while the colors (varying from yellow to red) reflect the different levels of significance. (B) Also the enrichment analysis performed with the same software, confirm the same altered metabolic nets.

Discussion

The metabolomics approach applied in this study allowed the identification of a set of hydrophilic metabolites that appears to represent a specific pattern characterizing the PANS condition. This pattern was independent of the gender of the patients, as demonstrated by our results. Moreover, through the statistical tools employed by this study we can hypothesize that the age of the enrolled subjects weakly correlate with changes in metabolic profile, while a significant correlation was found between the severity scale of PANS and the metabolic profile of the affected patients. The current lack of reliable biomarkers for PANS leads us to consider our data as an important starting point in understanding the pathological features of this complex syndrome. Metabolomics profiles are considered the omics layer most proximal to phenotype ( Patti et al., 2012; Haas et al., 2017): In contrast to genetic variants, metabolomics profile can be either a cause or a consequence of the phenotype of interest. Following this reasoning, analysis of the putative role of specific metabolites and altered pathways may help to define a comprehensive metabolic pattern of the disorder, which, in turn, may be of help in determining specific biomarkers.

The amino acid tryptophan (Trp) was found at significantly lower serum concentrations in patients with PANS than in controls. More interestingly, though, this metabolite also negatively correlated with the severity of the syndrome as demonstrated by the result of the Person correlation. The pathways analysis confirmed an alteration in Trp metabolism. In recent years, Trp metabolism has been increasingly recognized as central to the pathogenesis of many neuropsychiatric disorders. In particular, a decrease in Trp level was found in major depressive disorder ( Moreno et al., 2010; Liu et al., 2015), schizophrenia ( Yao et al., 2010; Xuan et al., 2011) and exhaustion disorder ( Hadrévi et al., 2019). Our findings are in line with these reports, suggesting that Trp metabolism may be common to several neuropsychiatric conditions that share several clinical features with PANS, such as irritability, anxiety, emotional lability and thought disturbances.

The predominant pathway of Trp metabolism in humans is the Kynurenine Pathway (KP) ( Dantzer, 2017): several tryptophan-kynurenine pathway metabolites have been increasingly recognized as crucial facets immuneregulatory mechanisms, neuroinflammation ( Mándi and Vécsei, 2012) and microglial activation, potentially related to severe neuropsychiatric disorders ( Horikawa et al., 2010) such as depression ( Dantzer, 2017), psychosis and Autism Spectrum Disorder (ASD) ( Olloquequi et al., 2018).

This putative mechanism is supported by studies on animal models; symptoms such as severe involuntary movement, increased locomotor activity and persistently impaired active avoidance learning, suggestive of a PANS-like phenotype, can be induced by administering quinolinic acid (QA), a potently neurotoxic metabolite of the KP, into the striatum ( Vécsei and Flint Beal, 1991).

As well as products of the KP pathway, tryptophan is also the precursor to 5-hydroxytryptamine (5-HT) ( Wichers and Maes, 2004). Given this, it is reasonable to assume a direct link between the two biomolecules. 5-HT has diverse roles in memory, mood, anxiety, aggression, pain, sleep, and eating behavior ( Sandyk, 1992). Accordingly, 5-HT deficit has been implicated in several neuropsychiatric illnesses ( Bell et al., 2001), including major depressive disorder, obsessive-compulsive disorder, and anxiety ( Baumgarten and Grozdanovic, 1998; Colle et al., 2020). Interestingly, several conditions involving Trp malabsorption (e.g., Hartnups disease) are often characterized by symptoms such as psychosis or depression ⁽Oyanagi et al., 1967), as well as dietary Trp deprivation having been shown to exacerbate ASD symptoms ( McDougle, 1996). Moreover, serotonin is the major substrate required for melatonin synthesis, and consequently, serotonin deficiency reduces the synthesis of melatonin ( Zimmermann et al., 1993). This suggests a possible explanation for the sleep disruption frequently occurring in PANS, described as parasomnias (nightmares, nocturnal pavor, sleepwalking or somnambulism), as well as difficulties in initiating or maintaining sleep (early or intermediate insomnia), early awakenings (terminal insomnia), REM sleep disorders such as REM Sleep Without Atonia (RSWA), and sleep movement disorders such as Periodic Limb Movement Disorder (PLMD) ( Santoro et al., 2018). Combined, these data strongly suggest that abnormal tryptophan metabolism may play a role in the pathophysiology of PANS since the presentation of PANS symptoms encompasses tics and anxiety, as well as obsessive-compulsive and psychotic symptoms.

Glycine is another metabolite significantly decreased in concentration ( p = 0.0048) in the serum of patients with PANS compared to healthy controls. The potential pivotal role of this metabolite in PANS was also confirmed by its direct correlation with the severity scale of this pathological condition. Glycine's biomolecular role is notable in several psychiatric disorders ( Rujescu and Giegling, 2016; Erjavec et al., 2018; Humer et al., 2020). Glycine is widely distributed in the mammalian CNS, functioning as an inhibitory or excitatory neurotransmitter, depending on its localization. Glycine is the main neurotransmitter in inhibitory interneurons of the spinal cord, brainstem, and in other brain regions involved in the processing of sensorimotor information and locomotor behavior ⁽Chatterton et al., 2002). Glycine can activate two classes of distinct ligand-gated ion channels: chloride-permeable inhibitory GlyRs ( Gielen et al., 2015) and cation-selective excitatory NMDARs. Electrophysiological, immunocytochemical, and in-situ hybridization studies have shown that GlyRs are prominent in the brainstem and spinal cord ( Altschuler et al., 1986; Alvarez et al., 1997) and detectable also in the following brain regions: the prefrontal cortex, hippocampus, amygdala, hypothalamus, cerebellum, nucleus accumbens, ventral tegmental area, and substantia nigra ( Ye et al., 1998; McCool and Botting, 2000; Chattipakorn and McMahon, 2002). As an excitatory neurotransmitter, glycine acts as a co-agonist of ionotropic NMDARs, allowing for depolarization, removal of the magnesium blockade, and Na⁺/Ca ²⁺ passage through the ion channel, which ultimately enhances the glutamatergic excitatory tone that is critical for learning and neuronal plasticity ( Nakazawa et al., 2004; Collingridge et al., 2013). Notably, the affinity of glycine for NMDARs is significantly higher than that of GlyRs (EC50 = 134 nM vs. EC50 = 270 mM) ( Chattipakorn and McMahon, 2002; Cubelos et al., 2014). Thusly, under physiological conditions, endogenous glycine may exert a mainly excitatory effect in the hippocampus, where both GlyRs and NMDARs are expressed. Interestingly, an increase in serum glycine levels measured by ¹H-NMR spectra has been shown to differentiate schizophrenia (with higher glycine levels) from bipolar patients (with glycine plasma levels similar to controls), suggesting an important role for glycine in regulating cognition ( Tasic et al., 2019) and affective regulation, an observation parallelled in animal models of neuropsychiatric disorders ( Humer et al., 2020). Irritability, emotional lability, behavioral regression has been shown to be a crucial component of the PANS clinical presentation ( Gagliano et al., 2020), rendering the involvement of glycine metabolism in PANS biologically plausible. Remarkably, antibodies directed against extracellular receptors on the synaptic surface, such as the NMDA receptor, are known to lead to NMDA receptor hypofunction in patients, resulting in behavioral and psychotic manifestations in specific forms of autoimmune encephalitis ( Endres et al., 2019).

Glutamine levels, and the activity of associated pathways (glutamine and glutamate metabolism and aspartate and glutamate metabolism), were also found to be lower in PANS patients compared to the neurotypical control group. Glutamine in the CNS plays an essential role in the glutamate/GABA-glutamine cycle; it is transferred from astrocytes to neurons, where it replenishes the inhibitory and excitatory neurotransmitter pools ( Masdeu et al., 2016). Decreased glutamine plasma concentrations may be caused by several factors, including acute inflammatory activity and consecutive distribution abnormalities, and therefore is not, per se, an indicator of actual shortage ( Leke and Schousboe, 2016). Glutamine is an essential nutrient in all rapidly proliferating cells, including immune cells; it provides many different building blocks for these cells and simultaneously maintains redox balance by providing reducing equivalents, which are also necessary to allow the appropriate functioning of the immune system. Glutamine supplementation may be beneficial in patients with a long-standing inflammatory activity that are not producing sufficient quantities of glutamine either due to malnutrition or because they cannot meet the demands of extremely severe inflammatory illnesses (e.g., in ICU patients). More precise information on glutamine's role in PANS could reveal innovative therapeutic approaches.

Histidine, which was also found to be at a significant deficit in PANS patients, is a precursor of the ubiquitously distributed neurohormone neurotransmitter histamine. In the CNS, histamine is known to regulate sleep and wakefulness, learning and memory, feeding, and energy ( He et al., 2012; Soeters and Grecu, 2012). A decrease in plasma histidine level has been considered a metabolomic signature of schizophrenia, although contrasting results have been reported on plasma and brain histamine levels ( Hu and Chen, 2017). Taken together, the significant decrease of histidine observed in the present study indicates the need for further investigation on a putative role of histamine in the pathophysiology of PANS; histamine levels were not measured in the present study, but the increasing availability of histaminergic receptor modulators supports interest in this neurotransmitter.

Finally, 2-Hydroxybutyrate was found to have significantly increased concentration in the serum of PANS patients. This metabolite is typically produced as a result of excessive glutathione anabolism ( Takahashi et al., 2006). Glutathione is an antioxidant whose synthesis has been demonstrated to undergo compensatory upregulation in the blood of individuals experiencing increases in oxidative stress, such as smokers ( Gall et al., 2010), as well as in the aging brain ( Agarwal et al., 2019). The 2-Hydroxybutyrate increase observed in this sample may indicate that oxidative stress may be considered a crucial feature of PANS.

The specific plasma metabolites observed in the present study might reflect particular changes in metabolic pathways induced by inflammation, blood-brain barrier breakdown, and dysregulation of energy metabolism. These processes may activate a common final pathway that can be triggered by different agents.

The results of the present study suggest unique plasma metabolite profiles in PANS patients, significantly differing from healthy children, showing abnormal levels of metabolites associated with neurotransmission (tryptophan, glycine, histamine/histidine) and generalized energy deficiency, oxidative stress, neuroinflammation (glutamine, 2-Hydroxybutyrate and, potentially, the tryptophan-kynurenine pathway). Overall, the evidence provided by the present study is consistent with the accumulating data supporting the presence of a neuroinflammatory component in several psychiatric illnesses ( Tong et al., 2016). Inflammatory biomarkers have been found in common neuropsychiatric outcomes ( Najjar et al., 2013), such as ADHD ( Yuan et al., 2019), ASD ( Dunn et al., 2019), bipolar disorder ( Xu et al., 2015), depression ( Muneer, 2016), and schizophrenia ( Dowlati et al., 2010; Na et al., 2014).

However, the present work is not without limitations. We focused on a homogeneous group of children and adolescents diagnosed with PANS; a comparison with patients presenting a limited association of two or more PANS criteria, but not the complete disorder, can strengthen our study.

Further analysis of patients with PANS, using additional methods, such as Mass Spectrometry, may be able to identify additional metabolites that cannot be detected by our NMR approaches, such as lipophilic compounds.

More in-depth investigation on a larger cohort with additional tools is needed to confirm these findings and support their interpretation. Nevertheless, our results strongly suggest the utility of metabolomics as a means to enhance PANS biomarker research. We argue that serum metabolites can ultimately provide a map of the regulation of the metabolic pathways in the central nervous system of individuals with PANS. This is due to the syndrome exhibiting altered mechanistic biochemical patterns, linked to exposure to an environmental stimulus (e.g., infectious agents or stressors) with the capability of disrupting metabolism. This, in turn, results in changes that can be captured as metabolic signatures potentially providing information with regard to PANS pathophysiology.

Conclusion

PANS is currently conceptualized as a complex syndrome with several etiologies and disease mechanisms, encompassing psychiatric symptoms and arising from inflammatory/immune abnormalities triggered by a variety of agents ( Swedo et al., 2012; Frankovich et al., 2015). The specific plasma metabolites observed in the present study might reflect specific changes in metabolic pathways induced by inflammation, blood-brain barrier breakdown, and dysregulation of energy metabolism. These processes may activate a common final pathway that can be triggered by different agents. In conclusion, the results of the present study suggest unique plasma metabolite profiles in PANS patients, significantly differing from healthy children, showing abnormal levels of metabolites associated with neurotransmission (tryptophan, glycine, histamine/histidine) and generalized energy deficiency, oxidative stress neuroinflammation (glutamine, 2-Hydroxybutyrate and, potentially, the tryptophan-kynurenine pathway). Taken together, our results strongly suggest the utility of metabolomics as a means to enhance PANS biomarker research.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics Statement

The studies involving human participants were reviewed and approved by COMITATO ETICO INDIPENDENTE Azienda Ospedaliero Universitaria di Cagliari P.O. San Giovanni di Dio: via Ospedale 54 - 09124 Cagliari Segreteria Tecnico Scientifica tel. 0706092547-0706092262-fax 0706092262 Web: www.aoucagliari.it/home/it/comitato_etico_.page. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

Author Contributions

FM and AG provided substantial contributions to the conception and design of the work, the analysis and interpretation of data for the work, and drafting of the work. MT and AH provided substantial contributions to patient recruiting, database collection, and acquisition and analysis of data. FCe, MP, and FCo managed the patient recruiting and the database collection. SC and SS revised the work critically for important intellectual content. NO-G, LA, and AZ revised the work critically for important intellectual content and gave their final approval of the version to be published. All authors contributed to the article and approved the submitted version.

Conflict of Interest

AG was on the advisory boards for Eli Lilly and Shire. She is/has been involved in clinical trials conducted by Eli Lilly, Shire, Lundbeck, Janssen, and Otsuka. She has been a speaker for Novartis, Eli Lilly, and Shire. SC was collaborating on projects from the European Union (7th Framework Program) and as a sub-investigator in sponsored clinical trials by Lundbeck Otsuka and Janssen Cilag. Travel support from Fidia Farmaceutici. AZ served in an advisory or consultancy role for Angelini, Lundbeck, Otsuka, and Edu-Pharma. He received conference support or speaker's fee from Angelini, Otzuka, and Takeda. He is/has been involved in clinical trials conducted by Angelini, Roche, Lundbeck, Janssen, Servier, and Otsuka. He received royalties from Oxford University Press, and Giunti OS. SS received conference support or speaker's fee from Bayer Pharma, Biogen Idec, Merck-Serono, Novartis, and Teva. He has been involved in clinical trials conducted by Bayer Pharma, Biogen and Teva. He received royalties from Documenta (Ed). The present work is unrelated to the above grants and relationships.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We thank Aneta Ewa Macudzinska and all the volunteers who participated in these clinical researches, as well as the physicians and study nurses who conducted the study.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnins.2021.645267/full#supplementary-material

Footnotes

References

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IntroductionPANS is a controversial clinical entity, consisting of a complex constellation of psychiatric symptoms, adventitious changes, and expression of various serological alterations, likely sustained by an autoimmune/inflammatory disease. Detection of novel biomarkers of PANS is highly desirable for both diagnostic and therapeutic management of affected patients.

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What is PANDAS?

PANDAS is short for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. It occurs in children and adolescents who show sudden - sometimes overnight - obsessive compulsive disorder (OCD) symptoms and/or tic disorders that are linked to a strep infection, such as strep throat and scarlet fever.

Symptoms of PANDAS

The symptoms of PANDAS can include:

Motor or vocal tics or both

Obsessions, compulsions, or both

In addition, other symptoms may include:

Restrictive eating

Anxiety attacks

Separation anxiety (i.e. child is clingy.)

Mood changes

Trouble sleeping

Changes in motor skills, such as changes in handwriting

Hyperactivity

What is PANS?

PANS stands for Pediatric Acute-onset Neuropsychiatric Syndrome. This medical condition describes acute OCD symptoms or restricted food intake along with other psychiatric or neurologic symptoms in children.

Unlike PANDAS, PANS is not limited to children with strep infections, but it is associated with a variety of different infections such as the flu, chicken pox, mycoplasma and Lyme disease. Both conditions, however, can cause a range of behavioral disturbances and neurologic problems.

Symptoms of PANS

Children with PANS have severe symptoms of OCD. Other symptoms may include:

Anxiety

Mood swings

Irritability

Uncontrollable movements

Bedwetting

Trouble sleeping

Decrease in school performance

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PANDAS & PANS - Autoimmune Disorders in Children

# data[].attributes.attachment_link.description
PANDAS is short for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. It occurs in children and adolescents who show sudden - sometimes overnight - obsessive compulsive disorder (OCD) symptoms and/or tic disorders that are linked to a strep infection, such as strep throat and scarlet fever.

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PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection) and PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) are infection-induced autoimmune conditions that disrupt a patient's normal neurologic functioning, resulting in a sudden onset of Obsessive-Compulsive Disorder (OCD) and/or motor tics. PANDAS/PANS can include a variety of other symptoms such as anorexia (food restrictions), anxiety, irritability, hyperactivity, sleep disturbances, mood swings and urinary problems.

October 9th is PANDAS/PANS Awareness Day, and PANDAS and PANS families across Canada are proud to support Canadian Blood Services during the month of October, in honour of our PANDAS/PANS children. https://pandascanada.wixsite.com/pandascanada

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PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection) and PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) are infection-induced autoimmune conditions that disrupt a patient's normal neurologic functioning, resulting in a sudden onset of Obsessive-Compulsive Disorder (OCD) and/or motor tics.

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"Completely overnight, my daughter is possessed by all these new obsessions and compulsions. This morning she spent an hour in tears rearranging her books over and over. And yesterday, she screamed about her clothes suddenly being too tight. She is petrified when I leave her, and she follows me around the house yelling at me to help her. But everything I do is wrong. She won't even eat her favourite foods, and last night for the first time since she was three years old she wet the bed! She's just not herself anymore. What's going on? What should I do?"

Both PANDAS and PANS are only recently becoming recognized by medical professionals, who in the past may have overlooked these conditions because of a lack of knowledge, and/or because how similar the symptoms are to other conditions (such as 'typical' OCD).

The prevailing hypothesis is that PANDAS is caused by an autoimmune response to a strep infection in the body. Interestingly, it is not the strep bacteria itself that is the culprit, but rather the body's immune reaction to the strep that is appears to be causing inflammation in certain areas of the child's brain (such as the basal ganglia).

PANS is a more recent and broader diagnostic category used when a bacterial infection other than strep is creating the autoimmune response and resulting inflammation in the brain. These infections include Lyme Disease, mononucleosis, H1N1, and mycoplasma.

For BOTH conditions, however, the key feature is that the inflammation is creating sudden and drastic behavioural and mood changes in a child. For example, children may start having (or have a noticeable increase in the severity of) obsessions and compulsions, tics (I.e. particular motor or vocal movements), extreme irritability and sensitivity, and in some cases, regression of developmental skills (e.g. poor handwriting, bedwetting). In contrast, in 'typical' Obsessive Compulsive Disorder or OCD, obsessions and compulsions develop more gradually and may take months or even years to become obvious to the sufferer and loved ones.

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Introduction on PANDAS and PANS - Anxiety Canada

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"Completely overnight, my daughter is possessed by all these new obsessions and compulsions. This morning she spent an hour in tears rearranging her books over and over. And yesterday, she screamed about her clothes suddenly being too tight. She is petrified when I leave her, and she follows me around the house yelling at me to help her.

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Our Services Include:

Individual support sessions, in person and online support groups, community awareness/educational presentations, and coordination of medical and educational resources.

Our Mission:

It is our mission to ensure that all children who present with the symptoms of PANDAS or PANS are screened for infection in a timely manner and that these families are supported along their child's path to healing.

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Individual support sessions, in person and online support groups, community awareness/educational presentations, and coordination of medical and educational resources. It is our mission to ensure that all children who present with the symptoms of PANDAS or PANS are screened for infection in a timely manner and that these families are supported along their child's path to healing.

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PANDAS PANS COSTS OF MISSED OR DELAYED TREATMENT

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Rep. John Bradford Recognizes PANS/PANDAS Awareness Day on House Floor

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Eliana Uku wasn't too worried when she got sick from COVID-19 in March 2020. She was 26 and healthy, she exercised most days, and at first her symptoms were mild. Even with a low fever, cough, fatigue, and mild headache, she kept working in her job as a corporate strategist in New York City. Three weeks after her first symptoms appeared she felt well enough to resume running.

But her cough persisted, and after a month or so, new symptoms appeared, such as memory lapses and sensitivity to sound. Everything was painfully loud, including the sound of her boyfriend washing dishes, leading the couple to switch to paper plates. She would forget words, and her mind would go blank at work meetings. By May she had insomnia, restless legs, and severe nausea. Her heart rate would skyrocket into the 160s after standing for a few minutes, even though she used to be a marathon-runner with a resting heart rate in the high 40s.

Scared and confused, Uku went to the emergency room in May 2020, where a doctor told her that some patients were reporting lingering or even new COVID-19 symptoms-a condition now called long COVID. Now, nearly two years after she first got sick with SARS-CoV-2, Uku still can't work, and she has had to defer admission to Stanford Business School.

With scientific studies ongoing and a definition in flux, long COVID continues to confuse and frustrate patients and healthcare providers. But estimates of the number of people who...

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As long COVID cases grow, clues emerge about who is most at risk

# data[].attributes.attachment_link.description
Eliana Uku wasn't too worried when she got sick from COVID-19 in March 2020. She was 26 and healthy, she exercised most days, and at first her symptoms were mild. Even with a low fever, cough, fatigue, and mild headache, she kept working in her job as a corporate strategist in New York City.

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Kate Porter, 36, and her daughter Adria, 12, still have symptoms, including severely elevated heart rates, shortness of breath and debilitating fatigue. "It's been a nightmare," says Porter. Credit... Adam Ferguson for The New York Times

Feature

Some patients could be living with the aftereffects for years to come. Recent research into another persistent, mysterious disease might help us understand how to treat them.

Kate Porter, 36, and her daughter Adria, 12, still have symptoms, including severely elevated heart rates, shortness of breath and debilitating fatigue. "It's been a nightmare," says Porter. Credit... Adam Ferguson for The New York Times

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When Mount Sinai Hospital opened its Center for Post-Covid Care in May, it was New York's - and the country's - first such facility. The doctors there expected to treat patients who had been severely ill or hospitalized. By that point, three months into the pandemic, they knew that the coronavirus could cause harm to many parts of the body beyond just the airways where infections most commonly begin. And they knew that medical treatments meant to save patients' lives could also take a toll. Recovery from having been put on a ventilator, in particular, could be a lengthy process. Mount Sinai sought to support patients recovering from severe Covid-19 by giving them access to a multidisciplinary medical team that included lung, heart and kidney doctors, rehabilitation specialists and psychiatrists for those whose mental health might have been affected by their ordeals.

Hundreds of patients, most of them women, showed up soon after the center's doors opened. To the doctors' surprise, however, many of them had experienced only mild cases of Covid-19. They hadn't been hospitalized. They were relatively young and otherwise in good health, without the underlying conditions like obesity and diabetes that are known to make Covid-19 worse. And yet, months after their bodies had seemingly fought off the coronavirus, they still felt quite ill. "We've heard of illnesses, viral illnesses, that have a prolonged postviral phase," Zijian Chen, the head of Mount Sinai's recovery center, told me. "But these usually don't last for the months and months that we see here. And because of that, we're a little surprised that this is happening. It tells us how much we don't know about this illness." The center has now seen more than 1,600 patients.

These patients have labeled themselves "Covid long-haulers." What they're suffering from, they say, is "long Covid." As a group, they report a strange hodgepodge of symptoms, including fatigue, pain, shortness of breath, light sensitivity, exercise intolerance, insomnia, hearts that race inexplicably, diarrhea and cramping, memory problems and a debilitating "brain fog" that can at times make it hard to put a cogent sentence together. In many cases, these symptoms continue unabated from the acute phase of the illness - as if, on some level, the infection never really went away. And for a subset of patients, new symptoms emerge later, as if a different illness has established itself in their bodies.

This was the experience of Lada Beara Lasic, a nephrologist who contracted the coronavirus in early April and later sought help at Mount Sinai's post-Covid center. After an initial three-week illness and some shortness of breath, she thought she had mostly recovered. She even returned to work - for one day, before she fell ill again with aches the following day. She tried working from home in May but was troubled by fluctuating symptoms that gradually worsened until, in June, she decided to take a leave of absence from her job to focus on her recovery.

Lasic, who is 54 and has been working a few hours a day from home since September, worries about the long-term consequences of what she suspects is an immune system that can't calm down. "We know that it's not good for the body to have inflammation," she told me. "It may cause scarring, and that means irreversible changes. The longer I have this disease and I'm inflamed, the worse it is for my health in the future."

Despite the crippling symptoms, it's often hard to figure out precisely what is wrong with patients like Lasic. Her blood work, for instance, has shown some signs of inflammation and elevated liver enzymes, but little else. "Many of these patients have had million-dollar work-ups, and nothing comes back abnormal," says Dayna McCarthy, a rehabilitation specialist at Mount Sinai. Hearts, lungs, brains - all appear to be functioning normally. Among the only things that can be said with any certainty about these patients is that they recently received a diagnosis of Covid-19.

At Mount Sinai, most patients improve with time, McCarthy told me. But the improvements can be maddeningly slow. And they're not universal. A small minority hasn't improved in the many months since the first wave of the pandemic crashed into New York City, she says. Some patients, including a few doctors and nurses, can no longer work, because they are too fatigued or have trouble focusing. Others have lost their jobs but can't get disability benefits because, subjective reports of misery aside, doctors can find nothing wrong with them. "Initially this was sold as a virus infection that only affects the elderly, and that is absolutely not the case," McCarthy says. "I can't think of anything worse than this type of symptomology that affects young people."

Zijian Chen estimates that about 10 percent of Covid-19 patients end up developing symptoms that persist for months and months - a number that would equate to roughly 100,000 chronically sick people in New York State alone. Some surveys suggest the number is higher. A study from Ireland found that more than half of Covid patients, whether they'd been hospitalized or not, reported fatigue 10 weeks out; nearly a third hadn't returned to work. In another study, from the Faroe Islands, about half the patients with mild cases had at least one symptom 18 weeks later. A third, much larger study, from China, reported that three-quarters of those patients who were hospitalized with Covid-19 and then discharged still experienced at least one symptom six months later.

The range of outcomes underscores how much remains unknown about this syndrome; it also suggests that the number of people who now find themselves constantly ill is probably significant. Recognizing this, scientists have begun studying Covid patients with chronic symptoms at the National Institutes of Health and elsewhere. And centers catering to these patients are opening or are in the process of opening around the country, including at NYU Langone, Yale and the University of Iowa.

For many doctors, the strange symptomology of long Covid calls to mind another mysterious, poorly understood condition: myalgic encephalomyelitis, more familiarly known as chronic fatigue syndrome. ME/CFS, as it is often abbreviated, is defined by the presence of certain symptoms, including debilitating fatigue and unrefreshing sleep, that last for six months or longer. ME/CFS-like syndromes have been linked with infections for more than a century - including, most recently, those caused by the viruses responsible for the SARS and H1N1 pandemics in 2003 and 2009. Chiefly because of this association, several ME/CFS experts told me that they anticipate a wave of new patients - long-haulers who, because their symptoms are severe enough and last for six months or longer, will essentially be ME/CFS patients whether they receive the diagnosis or not.

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"I'm expecting to see an increase that could generate as many new cases over the next two to three years as exist already in the U.S.," says Anthony Komaroff, a physician at Brigham and Women's Hospital in Boston who has treated ME/CFS for decades. In other words, as many as 2.5 million additional people could become afflicted with a disorder that some have argued causes more illness and suffering than H.I.V. "It's not death," Komaroff told me. "But might it be a fate worse than death for some people? It's possible."

The underlying biology of ME/CFS is poorly understood. Certain doctors long dismissed it as a psychological phenomenon, in part because no one could figure out what caused it. For this and other reasons, research into the syndrome has, in the view of many, not been commensurate with the great costs it exacts - tens of billions of dollars yearly in medical bills and lost productivity, to say nothing of the many lives spent hidden away, sometimes bedbound, in darkened rooms.

These days, though, the medical community increasingly accepts the condition as real, and doctors have even made some headway in managing its symptoms. No one yet knows what the relationship between long Covid and ME/CFS - itself an imprecise diagnosis - will prove to be. But some experts think recent advances in the study of ME/CFS, inconsistent and inconclusive though our understanding of it remains, may provide insight into what ails long-haulers and how to treat them. In the process, that research might also shed light on an enduring medical conundrum: Why do certain infections, even as they resolve in most cases, become a protracted, debilitating ordeal for a small group of unlucky patients?

Even as doctors around the world have been flummoxed by long Covid and its mysteries, the patients themselves have found one another online. Soon after the pandemic started, the medical consensus, based on the World Health Organization's analysis of China's experience, held that mild Covid-19 cases should resolve in two weeks on average. So, as patients with supposedly mild cases continued to experience symptoms long after that two-week mark - and in some cases actually got worse as time dragged by - they knew something was amiss.

They named themselves early on. "Long-haulers" originated with an American woman who started a support group and christened it the "long-haul Covid fighters," inspired by the trucker hat she was wearing when she was tested for Covid. "Long Covid" first emerged as a hashtag (#LongCovid), coined by an Italian in Lombardy, a hard-hit region of the country. Similar terms arose in Spanish (#CovidPersistente), German (#MitCoronaLeben) and other languages.

Many long-haulers report that medical professionals respond to them with disbelief or brush off their symptoms as merely psychological. Still, by September, the World Health Organization's use of "long Covid" signaled that the term had crept into mainstream medical awareness. Doctors had formulated their own phrasing as well: "post-acute Covid-19 syndrome."

When trying to treat what ails long-haulers, separating those with organ damage from the rest will be important, scientists told me. "There are some people whose heart and kidneys are not going to work as well for the rest of their lives," Anthony Komaroff says. This doesn't mean the damage cannot be treated. Doctors can prescribe aspirin and other drugs for the heart inflammation seen in some Covid patients, for example, or anticoagulants to help with blood clotting.

The more puzzling matter, though, is how to understand and treat the many patients who have little that's measurably wrong with them, or whose Covid-related injuries can't explain their malaise, but who nevertheless feel physically and mentally enervated.

In my conversations with them, long-haulers detailed bewildering post-Covid symptoms - new sensitivities to smells and tastes, brutal chest pains, migraines that felt like, in one woman's words, "someone stuck an ice pick in my head." But what often seemed most disturbing to patients were the deadening fatigue and cognitive issues that in some ways resembled dementia.

Lauren Nichols, who is 32 and fell ill in March, told me she had become so forgetful that she had to write notes to remind herself to eat. Once, in the shower, she sat on the floor weeping because she couldn't recall how the doorknob worked. "It takes me hours to write email and text messages," she says. Kristen Tjaden, who is 34, contracted the coronavirus in April. One time, months after the illness, she couldn't remember which hand was the left one. She found she couldn't do two things at once, like folding laundry and listening to music - the mental strain was too great. By November, things were gradually improving, but she just didn't feel "like this is my own brain," she told me then. The problem isn't so much brain fog, she said, as "a brain hurricane."

Scientists invariably mention the possibility that ongoing inflammation and perhaps autoimmune processes that result from having fought off the virus could drive the strange constellation of symptoms. Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke, told me that when fighting a pathogen, the immune system sometimes conducts a very precise and surgical attack, working like a guided missile. But when that approach fails, it can begin "blanket bombing," as he puts it. Once the infection is gone, tamping down the resulting firestorm can prove challenging. "You have persistent immune activation," he says. And that lingering inflammation could drive many symptoms.

This notion that infection can unbalance the immune system has often been invoked to explain the onset of autoimmune diseases - conditions in which the immune system attacks the very body it's meant to protect. Multiple sclerosis, for example, has long been associated with infection by the herpesvirus Epstein-Barr. Rheumatic fever, a potentially deadly autoimmune inflammation of the heart and brain, is caused by a strain of the same streptococcus bacterium that we know from "strep" throat. A form of autoimmune arthritis can erupt in human knees and other joints after infection by the bacterium that causes Lyme disease, Borrelia burgdorferi.

In recent years, scientists have come to realize that the symptoms of certain autoimmune diseases can even mimic psychiatric disorders. In anti-NMDA receptor encephalitis, for example, the immune system attacks glutamate receptors on neurons in the brain, sometimes provoking behavior that resembles what's seen in schizophrenia. It, too, can be triggered by viral infection. (It's treatable.) There's also a pediatric condition that is similar to obsessive-compulsive disorder called pediatric acute-onset neuropsychiatric syndrome, or PANS, that many think can be set off by infection.

Certainly there is abundant evidence that the coronavirus can goad the immune system into overreaction during the acute phase of infection. Some children (and adults) develop a multisystem inflammatory syndrome. Scattered reports suggest that the virus might trigger Guillain-Barré syndrome, a frightening autoimmune condition in which patients develop full or partial paralysis (though most eventually recover). Some scientists have suggested that an exaggerated immune response to the coronavirus, rather than the damage directly inflicted by it, is responsible for many Covid deaths. This sort of self-destruction is often described as a "cytokine storm."

Ignacio Sanz, an immunologist at Emory University, and his colleagues recently described more granular evidence of this self-attack in Covid-19. Compared with a healthy control group, they discovered, severe Covid-19 patients display high levels of antibodies directed at their own tissues - antibodies usually seen in lupus and rheumatoid arthritis, two autoimmune diseases. This does not necessarily mean that these patients have an autoimmune condition, Sanz stresses. Those same antibodies are found in healthy people. But not only are the levels of these antibodies relatively high in severe Covid-19; the cells that produce them also appear to be even more primed for aggression than they are in autoimmune disease. In his view, this dynamic hints at an immune system pushed into overdrive. Sanz suspects that in people who already have a propensity to develop autoimmune disorders, the virus may tip their immune systems into overt autoimmune disease.

The fact that most long-Covid patients are women may be an important clue in support of this hunch. In general, women are more likely than men to develop autoimmune disease. Akiko Iwasaki, an immunologist at Yale, has found that female Covid patients tend to mount a stronger response to the virus from T cells, which help defend against microbial invaders, than their male counterparts. Testosterone is a slight immune suppressant, which may explain this disparity between women and men - and perhaps why men are more likely to die from Covid-19. (The female members of many species outlive the males, possibly because they have superior immune systems.) But one disadvantage of a more forceful immune response may be a greater propensity to attack the self. "Women survive this," Iwasaki says, "but maybe there's a cost."

Iwasaki and her colleague Aaron Ring have, like Sanz, also identified what seems to be immune misfiring in Covid-19. But instead of looking for antibodies already associated with autoimmune disease, they used a new technique to search for any antibody, including previously unidentified ones, that might bind with some 3,000 proteins - out of tens of thousands - produced in humans. Their findings, reported in a December preprint, which has not yet been peer-reviewed, suggest a widespread autoimmune attack. Compared with subjects from the healthy control group, severe Covid-19 patients had elevated levels of antibodies directed at dozens of tissues, including the brain, the lining of blood vessels and components of the immune system itself.

Why some infections might cause the immune system to attack the body in certain individuals but not others is a longstanding medical mystery. It may be that proteins on the invading microbe resemble tissue in the human body, and that in pursuing the invader, some people's immune systems accidentally attack similar molecules in their own organs. This idea is called molecular mimicry.

But Ring told me that the sheer number and variety of self-directed antibodies he and Iwasaki discovered suggest some other process gone awry. Some antibodies they observed were directed at virus-fighting components of the immune system itself, and Iwasaki posits a "vicious cycle" that begins with the immune system attacking itself, undercutting its own antiviral response. The body tries to compensate by ramping up other defenses, but these aren't well suited to fighting viruses and cause extensive cellular damage. As injured cells burst and release debris, the immune system, already in a frenzy, turns against the debris as well, inflicting even more harm.

Some of those self-directed antibodies declined in number over the course of Ring and Iwasaki's study, indicating that they may subside naturally once the virus is defeated. But if the antibodies stick around in some individuals, they could drive an ongoing attack at various sites in the body, which might account for the symptoms of long Covid. If that proves to be the case, Ring says, potential treatments already exist, including rituximab, a powerful drug that selectively depletes antibody-producing B-cells.

How exactly might an autoimmune disease cause the fatigue, cognitive failings and other symptoms seen in those with long Covid? Patients with other autoimmune diseases, like rheumatoid arthritis and inflammatory bowel disease, often report debilitating fatigue and brain fog. They may even consider this fatigue to be worse than the pain or discomfort emanating from what's usually considered the site of attack - the joints and the gut, respectively. The chronic inflammation central to these diseases causes the fatigue, doctors think. It's an illustration of just how tightly connected the immune system is with our sense of well-being.

Long Covid and ME/CFS share features beyond symptoms. Both are linked with infection. And the immune system is a focus of research into both conditions. Yet the idea that long Covid and ME/CFS are overlapping disorders is not universally accepted. Although many long-haulers may now technically meet the criteria for ME/CFS, Maureen Hanson, a molecular biologist who studies ME/CFS at Cornell University, warns against assuming they are related. "We don't know how long people will actually remain ill," she says. And of course, there are thought to be millions of people around the world with ME/CFS, but "none of them got it because of SARS-CoV-2," she adds. "We don't know if this new virus will cause the same disease."

For patients, the "chronic fatigue" label carries the stigma of not always having been taken seriously by the medical establishment. But perhaps worst of all, the equation of the two conditions implies a scary permanence. "Chronic fatigue syndrome is a syndrome that does not get better," Dayna McCarthy says. "From a psychological perspective, that's just devastating." She counsels her patients not to read too much about ME/CFS on social media.

Even so, the similarities are numerous enough that Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, has raised them repeatedly, telling Medscape in July that "it's extraordinary how many people have a postviral syndrome that's very strikingly similar to myalgic encephalomyelitis/chronic fatigue syndrome. They just don't get back to normal energy or normal feeling of good health."

Scientists have for years considered three nonmutually exclusive explanations for how a viral infection might trigger ME/CFS: It changes the brain somehow, prompting ongoing fatigue and malaise; it becomes chronic, making the person ill indefinitely; or it triggers an autoimmune or inflammatory disease that continues to torment people long after the offending microbe is gone. These explanations feature in scientists' thinking on long Covid as well.

Yet for decades, physicians trying to treat ME/CFS have been bedeviled by one obstacle above all others: They have no way of objectively diagnosing the condition. Cardiologists see clogged arteries and consider heart disease. Infectious-disease doctors detect viruses and bacteria and think infection. But there is no equivalent, empirically measurable dysfunction that indicates ME/CFS. It "isn't a diagnosis - it's a label," Anne Louise Oaklander, a neurologist at Massachusetts General Hospital, told me. "We don't really understand what the underlying biology is."

In order to apply that ME/CFS label, a physician must first rule out other possibilities. Then a patient must satisfy three criteria, which are subjectively reported: incapacitating fatigue lasting more than six months; worsening symptoms after physical or mental exertion; and unrefreshing sleep. A fourth requirement is that patients suffer from at least one of the following: difficulties with thinking and memory; or orthostatic intolerance, a debilitating dysfunction of the autonomic nervous system characterized by rapid changes in heart rate and blood pressure when standing.

Even if scientists aren't sure about the root cause of ME/CFS, however, numerous studies in recent years have documented biological differences in these patients. There's orthostatic intolerance, for one - which, as one scientist pointed out to me, can't be "psychological." And Nancy Klimas, a physician and scientist at Nova Southeastern University, and others have observed that one set of cells in particular, called natural killer cells, behave quite strangely in ME/CFS patients. Normally these cells sidle up to and destroy cells infected by viral invaders. But in ME/CFS patients, Klimas has found them to be listless and inert. She doesn't think that they're defective; she hypothesizes that they've been worked to exhaustion.

Klimas's research on postexertional malaise - which has involved collecting blood work on volunteers before, during and after mild exertion - has also revealed numerous differences compared with healthy people. Some inflammation after exercise is normal. But that immune activation is quickly brought under control, and an anti-inflammatory signal eventually prevails. In ME/CFS patients, that inflammatory spike continues unabated. The patients seem to respond to exercise as if they were fighting the flu. "You can imagine what that feels like, like getting hit by a truck," Klimas says.

ME/CFS (and long-Covid) patients can suffer from dysautonomia, an affliction of the autonomic nervous system that can cause racing hearts, gut problems, dilated pupils, sweating and rapid changes in blood pressure when at rest. It may be one reason they don't feel rested after sleeping. The sympathetic nervous system - that part of your body that swings into action when, for example, you're chased by a bear - seems to have been permanently switched on in some patients. "Flight-or-fight all the time is not healthy," Klimas says.

Perhaps spurred by the sense that a storm of chronic illness is gathering, the National Institute of Allergy and Infectious Diseases hosted a video meeting in December devoted solely to long Covid, with the goal of sharing what was known about the condition and also identifying what remained unknown. Physicians and scientists from the United States and elsewhere spoke, as did some patients. And Peter Rowe, director of the Children's Center Chronic Fatigue Clinic at Johns Hopkins University, urged his fellow physicians to familiarize themselves with ME/CFS. Even if the root cause isn't well understood, doctors have learned a lot about how to manage some symptoms in recent years, he said, particularly orthostatic intolerance, which is common in both young ME/CFS patients and the few long-Covid patients he has seen so far.

Rowe told me he is concerned that the health care workers who will be involved in the long-haulers' rehabilitations won't know what ME/CFS specialists have learned. He frets that physicians aren't aware, for example, that too much physical exertion can drastically worsen symptoms. And he worries about the historical tendency to see the condition as psychological in nature. That thinking led to an overemphasis on treatments like cognitive behavioral therapy or graded exercise therapy, he says, which have largely been abandoned as cure-alls for ME/CFS in the United States, but not without first doing great harm to patients. "It's going to be extremely important not to make the mistakes that were made in the early '90s," he said at the meeting. As he put it to me: "I'm concerned that people haven't learned the lessons of the past 25 years."

Scientists have known for many decades that infections can trigger long-lasting, often debilitating conditions - ones that feature fatigue and cognitive dysfunction similar to what doctors are observing today in Covid-19 survivors. In other words, long Covid may simply be the latest example of a postinfectious phenomenon that has mystified physicians for more than a century.

The "Russian flu" pandemic that occurred between 1889 and 1892 left in its wake a now-familiar-sounding collection of symptoms, including pain, numbness and fatiguelike complaints described as "prostration" and "inertia," Mark Honigsbaum writes in his 2013 book "A History of the Great Influenza Pandemics." He quotes Josephine Butler, the British women's rights crusader, who declared in 1892, three months after contracting the virus: "I am so weak that if I read or write for half an hour I become so tired and faint that I have to lie down." Survivors of history's worst influenza pandemic, the so-called Spanish flu of 1918-19, also reported lingering symptoms, including "loss of muscular energy," "apathy" and "melancholia" that sometimes lasted for years.

Much smaller outbreaks of similar disorders occurred with remarkable regularity throughout the 20th century, with the notable difference that no one really knew what gave rise to them. In 1934, nearly 200 doctors and nurses in Los Angeles came down with what doctors labeled "atypical poliomyelitis" - "atypical" because, unlike true polio, it struck adults rather than children and caused neither death nor paralysis. Yet some patients regarded the long-lasting symptoms, which included pain, sleeplessness and difficulties with concentration and memory, as worse than the original illness.

In 1956, after an outbreak in London, British doctors coined the term "benign myalgic encephalomyelitis" to describe the condition, which, in medical speak, roughly means "muscle pain with brain and spinal cord inflammation." Most of these patients recovered, but not all. In London, 7 percent remained hospitalized three months later. After an outbreak in Iceland, doctors found that only 31 percent had recovered six years later.

Doctors proposed that a milder relative of the poliovirus must be at fault. But perhaps because no such virus could be identified, a rival explanation gained currency. In 1970, two British doctors reviewed records from 15 outbreaks and dismissed the idea of an infectious cause. Instead, they concluded that "either mass hysteria on the part of the patients or altered medical perception of the community" could explain the phenomenon. To support the "hysteria" claim, they cited the fact that most patients were women. The resulting shift in how doctors thought about the disease would, some have since argued, inflict tremendous harm on patients suffering from a very real, if ill-defined, disease.

In 1985, after another apparent outbreak in Incline Village, Nev., near Lake Tahoe, the media piled on, derisively calling the condition the "yuppie flu" - or as Newsweek described it in 1990, "a fashionable form of hypochondria." About this same time, scientists who were studying the condition settled on "chronic fatigue syndrome" to describe it. The term still rankles many who see it as greatly understating the severity of their condition. As the author Laura Hillenbrand, who has the illness, once told The Times, it "is condescending and so grossly misleading. Fatigue is what we experience, but it is what a match is to an atomic bomb."

After pursuing what seemed like promising leads, the quest to identify a single infectious cause of these persistent illnesses - the proverbial chronic fatigue virus - ultimately turned up little, and in 1992, a group of scientists, including Anthony Komaroff, advanced a more complicated if less satisfying explanation. "We think that this is probably a heterogeneous illness that can be triggered by multiple different genetic and environmental factors," they wrote, "including stress, toxins and exogenous infectious agents." In other words, the disease emerged from an interaction between each patient's unique makeup and any number of stressors in the environment - including, possibly, an infection.

In the 2000s, researchers in rural Australia tried to confirm through direct observation the proposed link with infection. Previously, scientists studying the syndrome were always playing catch-up, trying to figure out what had happened to patients who showed up at their offices already ill. But in the township of Dubbo, scientists collaborated with local doctors to follow 253 patients who contracted infections more serious than the common cold - those viruses weren't linked with ME/CFS - in order to see who might develop fatigue and other symptoms over the following year.

The scientists found that Dubbo residents could develop chronic fatigue after several illnesses, among them Q fever, which is caused by bacteria carried by livestock; Ross River fever, spread by mosquitoes; and Epstein-Barr infection, transmitted via human saliva. About 11 percent of the patients who contracted one of these infections still had symptoms six months later, at which time they met the criteria for chronic fatigue syndrome. Nine percent had persistent symptoms a year later. No social or psychological factors foretold who developed long-term fatigue and other symptoms. But one factor was broadly predictive: how sick patients became during the initial phase of their illness. The sicker they got, the more likely they were, after the infection itself had cleared up, to develop fatigue, pain and problems with memory and concentration.

From the Russian Influenza to Covid-19, these have been the abiding questions: Where in the body is the dysfunction that drives these chronic symptoms? And what distinguishes those who develop these long-term syndromes from those who don't? A study conducted several years ago by Alice Russell and Carmine Pariante at King's College London suggests that the answer may lie in the different ways individual immune systems respond to the same challenge.

Russell and Pariante decided to follow 55 subjects being treated for hepatitis C, a chronic viral infection of the liver. They wanted to see if any of them developed persistent problems not from the hepatitis virus itself but from the therapy meant to cure it. At the time, treatment included injections of interferon-alpha, a protein also made by our own bodies, which activates the body's antiviral defenses. By giving patients interferon, doctors essentially rev up their immune systems in much the same way an actual viral infection does. For years, scientists have known that interferon treatment can also lead to fatigue and depression in some patients. The therapy for these patients thus provided a way to simulate infection and then study its long-term consequences without using an actual infectious agent.

Six months after the treatment concluded, one-third of the patients reported persistent fatigue. At that point, nothing appeared to be different about their immune function. But by analyzing inflammatory markers in blood taken before and during the interferon therapy, the scientists found two rough predictors: the more activated their immune system was before treatment, and the more inflamed they became during treatment, the greater the likelihood of suffering from fatigue months later.

"It may be that in one person, the immune system is more reactive," Pariante says, "so it doesn't go back easily to normal after the challenge. And this is the person more likely to develop long-term fatigue."

This relationship may be present in Covid-19 as well. Pariante points to a study from Vita-Salute San Raffaele University in Milan showing that levels of inflammatory markers during a coronavirus infection roughly predicted the development of anxiety and depression after. (Depression is not the same as fatigue, of course, but scientists have for years hypothesized that aberrant inflammation is responsible for some cases of depression, just as they consider it a possible cause of ME/CFS.)

It still remains unclear, though, what biological dysfunction underlies those persistent symptoms after interferon treatment (or an actual infection) has run its course. This is the mystery at the heart of those ME/CFS cases associated with infection, and maybe long Covid too: How does an infection change your body so that you continue to feel terrible, and maybe even worse, long after the infection has gone? And why can't scientists pin down whatever that change is?

Pariante and others suspect that something may shift in the brain itself, where it's harder to detect anomalous immune activity. Two very small studies have documented brain inflammation in ME/CFS, one using positron emission tomography and another employing a technique called magnetic resonance spectroscopy. As always, in purely observational studies like these, it's unclear if what's different about these patients - the brain inflammation - actually causes the condition, results from it or is unrelated to it.

But scientists know that certain cells in the brain, called microglial cells, can assume different personas: They can function like agreeable handymen, removing detritus and ensuring that your synapses are clean and working properly. Or they can act like vandals, interfering with the brain. In animal studies, the shift is visible under a microscope, says Jarred Younger, director of the Neuroinflammation, Pain and Fatigue Laboratory at the University of Alabama at Birmingham, and the senior author on one of those brain-inflammation studies. With repeated infectious hits, microglia can become "spiky." "They look angry," he says, "like they're ready to fight."

Younger thinks that in ME/CFS, these cells may permanently change into that "angry" version of themselves. He is currently studying the possibility and, should that work pan out, he has a few drug candidates that might calm microglia. These include low-dose naltrexone, a drug that blocks opioid receptors and is sometimes used to treat autoimmune disease - and also been found to be effective, anecdotally, in ME/CFS - as well as minocycline, an old antibiotic that scientists know can exert an anti-inflammatory effect in the brain.

Another explanation for misfiring immune systems - one that some researchers put forward to explain long Covid - is that infection triggers an autoimmune disease, and that scientists have simply been unable to pinpoint where that self-attack is directed. Carmen Scheibenbogen, head of the chronic fatigue center at the Charité university hospital in Berlin, thinks she may have identified the target tissue. Some ME/CFS patients have an autoimmune disease in which antibodies interfere with certain receptors in the endocrine system, she thinks - precisely the kind of molecular self-laceration that might hamper the autonomic nervous system, producing the rapid pulse and other odd symptoms often seen in ME/CFS patients. Importantly, she and others have had some very preliminary success treating the problem as an autoimmune disease. If some portion of long Covid cases turn out to have the same or similar condition, her research may have much broader bearing.

Unfortunately, though, no single treatment is likely to cure all cases of ME/CFS. Scheibenbogen, Younger and other ME/CFS experts I spoke with were in agreement: The entity we call ME/CFS probably has multiple causes. "It's very unlikely this is a single disease," Younger says. "It's a few things."

Maybe the simplest explanation for why some long-haulers aren't recovering is that, even if they test negative, they may in fact still harbor a Covid infection somewhere in their body. Amy Proal, a microbiologist with the PolyBio Research Foundation, which focuses on chronic inflammatory diseases, thinks that if people feel sick after an infection, that may be because they in fact are still fighting a hidden infection. "An incredibly logical explanation is that the driving factor is still there," she says.

The idea of a persistent Covid infection remains unproved, although several studies hint at the possibility. But if this turns out to be the case for some patients, it will be important to separate them from those who might have an autoimmune or inflammatory condition, Proal points out, because treating one could aggravate the other. Using immune suppressants to treat an autoimmune condition, for example, could very well make a lingering infection worse.

The notion that long-term infection is responsible for chronic illness has an extensive history in ME/CFS research, where herpesviruses, which establish a lifelong presence in our bodies, have been put forward as the possible culprit. Nancy Klimas of Nova Southeastern University has gradually moved away from the suggestion that herpesviruses directly cause ME/CFS, though. Her view is that they play a secondary role. She suspects that, in some cases, ME/CFS consists of a two-phase illness: an initial hit of some sort - infection or trauma, say - and then, because that stressor lowers immunological vigilance, a second phase in which herpesviruses already present in the body may spring back to life and lead to misery. And then for reasons no one understands, the immune system can't get that second viral rebellion back under control. "The issue isn't the virus," Klimas says. "The issue is immune surveillance." The problem isn't necessarily their presence in our bodies, in other words, but rather that, after some destabilizing event, the immune system may lose the ability to manage viruses it easily handled before.

Anecdotally, at least, some long-haulers are experiencing the type of viral reactivation Klimas describes. In late October, seven months after contracting the coronavirus, Lauren Nichols developed shingles - a reactivation of the virus that causes chickenpox. The episode, which featured burning, "out of this world" nerve pain, sent her to the emergency room. A lesion developed on the cornea of her left eye, threatening her vision. Antiviral medication helped bring the shingles under control. Nichols, an administrator of a long-Covid support group, told me that reactivation of Epstein-Barr, cytomegalovirus and other herpesviruses occurs in a small but significant percentage of long-haulers on the site.

A similar argument over what drives chronic symptoms - persistent infection versus lingering inflammation from a past infection - appears prominently in the study of Lyme disease. Some people infected with Borrelia burgdorferi, the tick-borne bacterium that causes Lyme, fail to recover even after antibiotic treatment. Patients may refer to this illness as "chronic Lyme disease," but doctors prefer to call it "post-treatment Lyme disease syndrome," because they're not sure an infection is still really there. As in ME/CFS research, the debate over the root cause of this post-Lyme illness has for years polarized the field.

There are other similarities as well. The Lyme problem is underrecognized but immense. Every year, an estimated 329,000 people are infected by B. burgdorferi. About 10 percent of those treated with antibiotics develop lasting symptoms, including fatigue, pain and occasionally nervous-system conditions like dysautonomia - heart rate, blood pressure and other basic bodily functions in disarray. It appears to strike women more than men, it has long been dismissed as psychological and the long-term illness is often judged worse than the acute infection.

Like ME/CFS, post-Lyme syndrome has no biological marker that allows for concrete diagnosis. The three nonmutually exclusive ideas about what causes long-term symptoms roughly correspond with those for ME/CFS: a persistent infection (or perhaps merely debris from the Lyme spirochetes); an autoimmune or inflammatory dysfunction triggered by the infection that continues after the bacteria are gone; or changes in the nervous system that mirror Jarred Younger's "angry microglia" idea, but that are described by Lyme researchers as "central nervous system sensitization." Perhaps the infection changes how the brain works in such a way that once-easily bearable stimuli - pain, light, sound - become unbearable.

The parallels between ME/CFS and Lyme reinforce the notion that many different infections - including the Lyme spirochete - can trigger debilitating long-term syndromes. It's a lesson that we as a society have perhaps forgotten, Allen Steere, a Lyme expert and rheumatologist at Harvard Medical School, told me. "Now we have millions infected, and it becomes apparent to people that this type of problem can follow."

It's a maddening prospect, but long Covid may not be a single syndrome at all. It could, as seems to be the case with ME/CFS, be an array of problems connected in various ways with an initial trigger - in Covid's case, the invasion of the human body by a virus thought to be originally native to bats. ME/CFS doctors and researchers have faced this sort of frustrating complexity for years. It's an unavoidable challenge in managing a condition, be it ME/CFS or long Covid, whose diagnosis is based almost entirely on the subjective reporting of symptoms. There are, after all, many ways to produce symptoms like fatigue, brain fog and even dysautonomia. As Peter Rowe puts it, treating ME/CFS is like peeling an artichoke. "You're trying to remove treatable layers of problems and see what the essence is," he told me.

In the case of ME/CFS, scientists have identified a few more leaves of the proverbial artichoke - a grab bag of treatable, somewhat obscure conditions that seem to be associated with it. One is mast cell activation syndrome, which can produce fatigue, pain and problems with thinking and memory; infection can sometimes initiate it. Another is small-fiber neuropathy, a condition in which the body's nerves begin to misfire and can die off, causing pain, fatigue and disruption to basic bodily functions like breathing. Infections can sometimes trigger it, and given the current description of long-Covid symptoms, Anne Louise Oaklander, a pioneer in understanding this neuropathy, suspects it will be found to occur among long-haulers as well. "Small-fiber neuropathy is usually treatable," Oaklander told me, "and in some cases curable."

Long-haulers who contracted the novel coronavirus early in the pandemic are just about to round the one-year mark. Only with time will scientists be able to determine if long Covid and ME/CFS are the same or overlapping syndromes, or whether they're distinct and unrelated. For some ME/CFS specialists, however, long Covid already seems like a variant of the condition they've spent their careers treating. Carmen Scheibenbogen told me that in her experience, 1 to 2 percent of all patients infected with coronavirus meet the criteria for ME/CFS six months later. In New York, Susan Levine, an infectious-disease doctor who specializes in ME/CFS, finds that long-Covid patients respond to some of the same treatments that help ME/CFS patients, including low doses of naltrexone, which is anti-inflammatory.

But she does point out that long-Covid patients differ in subtle ways. Among ME/CFS patients, new complications can emerge slowly. Long-Covid patients see new symptoms develop relatively quickly. "It all happens in a compressed way," Levine told me. "The only silver lining is that I feel we can get these people earlier, soon after the Covid infection, as opposed to the ME/CFS patients, who languished for years."

The other possible silver lining, one expressed repeatedly by scientists and patients alike, is the prospect that the explosion of long-Covid cases will spur research, and that that research could yield treatments that may help the long-suffering ME/CFS community. "The disease has been ignored for decades and misjudged as a psychiatric disease," Scheibenbogen says. "We hope now that we get the awareness and money for research - and pharmaceutical drugs."

For the first time, scientists can follow thousands of patients infected by the same virus at roughly the same time. Funded by the C.D.C., Nancy Klimas has begun a study on long-haulers in which she hopes to prevent ME/CFS from taking root altogether. "We often talk about the three-year mark as people shifting into long-term illness," she told me. She plans to intervene with drugs before that milestone and hopefully prevent whatever it is that becomes self-perpetuating in ME/CFS.

Long-haulers may have one comparative advantage, at least: Whereas their ME/CFS counterparts in the past may have felt isolated and bereft of information, long-haulers live in a connected world. They've already been remarkably adept at organizing and making themselves heard, writing opinion pieces in major medical journals and media outlets, even conducting their own research.

If nothing else, the online organizing has been hugely important for some patients' mental health. Lauren Nichols told me that, early on, she contemplated suicide because few - neither doctors nor friends - believed her when she detailed her symptoms. (Those with ME/CFS have an elevated risk of suicide.) She connected with others who were going through similar experiences only after reading an April Op-Ed in The New York Times. The author, Fiona Lowenstein, had started a support group on her queer feminist website, Body Politic. Nichols rushed to join and quickly became an administrator. "My mental state changed - I said, 'Oh, my God, I'm not crazy,'" she told me. "The Body Politic support group prevented me from killing myself. And I really mean that."

Now, as we face the worst but hopefully final wave of the pandemic, many people - long-haulers, those with ME/CFS, scientists and doctors - worry about the long-term consequences of tens of millions of people infected with a virus that, it seems, can inflict lasting damage on the body. The palpable fear is that years from now, after the dead have been buried and victory over the coronavirus declared, some long-haulers will continue to suffer; and that their ongoing ordeal will be reckoned among the pandemic's more awful, lasting legacies.

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What If You Never Get Better From Covid-19? (Published 2021)

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Feature Some patients could be living with the aftereffects for years to come. Recent research into another persistent, mysterious disease might help us understand how to treat them. Kate Porter, 36, and her daughter Adria, 12, still have symptoms, including severely elevated heart rates, shortness of breath and debilitating fatigue.

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PANS/PANDAS - Children's Lyme Disease Network

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Lyme disease has been identified as one of the many infections capable of triggering a condition termed, pediatric acute-onset neuropsychiatric syndrome (PANS). The disorder, which effects children and adolescents, can cause debilitating symptoms, including OCD, eating disorders, anxiety, mood swings, and attention deficit disorder. PANS and Lyme disease also share similarities.

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PANS and PANDAS syndrome: GPs and parents call for more research into rare illness | 5 News

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Your generous donation will allow PANDAS Network to continue their dedication to improve the diagnosis and treatment of children with PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) and PANS (Pediatric Acute-onset Neuropsychiatric Syndrome).

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Excellent resource for parents

I purchased this book as part of my research on PANS. It was very helpful to have a parent's perspective, and a parent who was learned the hard way no less. Even without the P/P diagnosis, I found that much of the insight could be applied to other complicated pediatric health journeys.

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The Parent's Survival Guide to PANDAS/PANS

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Excellent resource for parents I purchased this book as part of my research on PANS. It was very helpful to have a parent's perspective, and a parent who was learned the hard way no less. Even without the P/P diagnosis, I found that much of the insight could be applied to other complicated pediatric health journeys.

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Understanding ContinuumRx’s IVIG Treatment for PANDAS/PANS | ContinuumRx

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A solution for children impacted by infections like STREP + Metabolic Disturbances The PANDAS Network estimates 1 in 200 children may have PANDAS/PANS. For many patients, intravenous immunoglobulin (IVIG) therapy which is made up of antibodies found in plasma is the right choice. Especially useful i…

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Raising awareness of PANS and PANDAS | A 5 News Tonight Special

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A heartfelt and moving performance of 'Fix You' by Coldplay, beautifully performed by Tim Friers and the Mercenaries with Sonia Serrano for PANS PANDAS UK.

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A heartfelt and moving performance of 'Fix You' by Coldplay, beautifully performed by Tim Friers and the Mercenaries with Sonia Serrano for PANS PANDAS UK.

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Personal video accounts from families experiencing the realities of PANS PANDAS and the lack of support available in the UK for the children with this condition

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Catching the Growth of the Cannabis Industry

The global stance on cannabis is changing rapidly.

With a wave of medical and recreational legalization occurring, there are now 70 countries with some form of legalization. As billions of investment dollars pour in, the cannabis industry finds itself entering a brand new chapter.

This infographic from eToro provides key information for investors on how the global cannabis market is making significant strides forward.

The World's Legal Cannabis Markets

In just a few short years since legalization momentum kicked off, societal views on cannabis have changed tremendously. Examples of this include:

Dispensaries being deemed essential businesses during the pandemic.

Uber announcing its intention to incorporate cannabis deliveries.

Malta becoming the first country to legalize cannabis in Europe for recreational use.

This shifting dynamic is part of why the global cannabis industry now generates over $20 billion in legal recreational sales on an annual basis.

The title for the world's largest cannabis market belongs to the U.S.-generating more than $16 billion in sales in 2020. However, their regulatory landscape is also one of the trickiest to navigate, as federal legalization has yet to occur despite over 30 states having legalized cannabis in some form.

While this unique situation leaves a lot of potential money off the table, it also provides lots of potential upside for the industry should legalization trends persist. In 2022, Mississippi, Oklahoma, and Delaware are considered likely to legalize, which would take the small tally of states without any form of legal cannabis from 14 to 11.

Here's how cannabis sales figures compare in various regions around the world:

This multi-billion dollar market is supported by a robust supply chain consisting of growers, retailers, support systems, and biotechnology companies. Each will become more vital, as the industry continues to grow and elevate to new highs. In 2020, consumer spend crossed past $20 billion, and will spike towards $37 billion by 2023.

But that's just the beginning of the growth story.

Key Trends to Watch

Compared to other industries, cannabis has had a very slow start. For decades, innovation has been relatively idle given factors like prohibition which has lasted for nearly 90 years.

But nowadays, a swath of new cannabis products and technologies are hitting dispensary shelves.

For instance, the Californian market saw 7,000 additional new products in 2020 compared to 2019. Put another way, there was an average of 19 new products in dispensary shops, daily.

What's more, some of these innovations can be seen in product popularity ranks:

Product Category

Estimated Sales 2021

Estimated Sales 2022

% of Sales 2022

Flower continues to dominate as the traditional method to consume. However, non-combustible methods like edibles and vape products have gained traction more recently, with vapes expected to see a 30% rise in sales in 2022. In addition, CBD products are growing fast in popularity, especially amongst women who make up 60% of CBD sales.

In the years to come, thousands of additional new products and technologies will pop up, suggesting that product preferences may continue to adapt.

A Bright Future For Cannabis

The cannabis industry's momentum has stirred up investor interest across the board. This can be seen through the average size of cannabis equity capital raises, which has grown 165% from $7.5 million in 2020 to $19.1 million in 2021. Momentum can also be seen through the cannabis stock indexes, which are showing signs of recovery.

But where does cannabis go from here? Things are moving rapidly, and by 2024, the global cannabis space is expected to be worth a massive $103 billion. Europe and North America will make up the largest components of this market, valued at $39.1 billion and $37.9 billion, respectively. But other regions are also forecasted to demonstrate some impressive numbers.

Here's what the forecasted 2024 global legal cannabis market will break down:

At over $100 billion, the cannabis industry's market value can potentially eclipse that of online betting and gaming.

How Can Investors Take Part?

eToro's CannabisCare Smart Portfolio* gives investors direct access to the growing cannabis market.

Curated by experienced and proven investment teams, the thematic portfolio offers exposure to a broad range companies invested in cannabis, with no management fees.
*Your capital is at risk.
Smart Portfolios is a portfolio management product, provided by eToro Europe Ltd., which is authorized and regulated by the Cyprus Securities and Exchange Commission. Smart Portfolios should not be considered as exchange traded funds, nor as hedge funds.

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Autoimmune Disorders: Is Your Child At Risk of PANS or PANDAS?

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The global stance on cannabis is changing rapidly. With a wave of medical and recreational legalization occurring, there are now 70 countries with some form of legalization. As billions of investment dollars pour in, the cannabis industry finds itself entering a brand new chapter.

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Insomnia, out-of-control tantrums, separation anxiety, rage, obsessions, disordered eating, paranoia, motor and vocal tics.

As a therapist or parent, have you come across a child exhibiting any of these behaviours and wondered if there was more to it than psychosocial, developmental or family dynamic issues at play? Have you known a child who used to be a great student but is now barely coping with school work because they can't focus, and has difficulty processing or remembering what they have learnt? Have you been left frustrated at the poor response to treatment? If so, you may have met or know a child who has paediatric acute-onset neuropsychiatric syndrome ( PANS) or paediatric autoimmune neuropsychiatric disorder associated with streptococcal disease ( PANDAS).

Unfortunately, most children with PANS/PANDAS are misdiagnosed as having psychiatric illness, behaviour problems, or parenting/family dynamic concerns. Many go through a number of psychiatric medications and therapies with minimal improvement, and many progressively get worse. A diagnosis of PANS or PANDAS should be considered whenever symptoms of OCD, tics, and eating restrictions start suddenly and are accompanied by other emotional and behavioural changes, frequent urination, motor abnormalities and/or handwriting changes (Calaprice, Tona, & Murphy, 2017). PANS/ PANDAS is also characterised by a relapse and remission pattern-children with PANS/PANDAS seem to have dramatic ups and downs in their symptoms, and an increased severity of symptoms is often correlated to a return of infection ( PANDAS Physicians Network, 2017).

PANDAS and PANS describe a subset of paediatric onset obsessive compulsive disorder (OCD). PANS may also be a subset of avoidant/restrictive food intake disorder ( PANDAS Physicians Network, 2017). It is considered a neuroinflammatory encephalitis that can have a number of infectious and non-infectious triggers (O'Hara, 2015). The syndrome is thought to be an immune reaction to various physiological stressors that include infectious agents such as group A streptococcal, mycoplasma pneumonia, influenza, human herpesvirus 6 (HHV-6), herpes simplex virus (Type 1 and 2), parvovirus B19, coxsackievirus, Lyme disease, Epstein-Barr virus, cytomegalovirus and candida (Song, 2017). Non-infectious agents include certain metabolic conditions (diabetes, lupus cerebritis), hormonal changes, environmental exposure to heavy metals, mould toxins, and psychological stressors (O'Hara, 2015). PANDAS is a subset of infection-triggered PANS caused by streptococcal infection (Calaprice et al., 2017). PANS and PANDAS symptoms can vary and do not necessarily present with an acute and dramatic onset (Song, 2017). Not rare, but rarely diagnosed due to poor awareness, it is estimated that 1 in 100 children are affected by PANDAS/ PANS (Song, 2017). By definition, PANDAS is a paediatric disorder typically first appearing in childhood from age 3 to puberty; however, it is possible that adolescents and adults may have immune-mediated psychiatric disorders such as OCD (Autoimmune Encephalitis Alliance, 2016). The combination of autoimmunity and behaviour is a relatively new concept linking the brain, behaviour, and neuropsychiatric disorders with infections and immune activation (Cunningham, 2014).

The bacteria associated with PANDAS are known as group A beta-haemolytic streptococcus (GABHS). Sites of streptococcal (strep) infection include: the throat, tonsils, adenoids, skin (eczema, psoriasis), urinary tract, gastrointestinal tract, and sinuses. In addition, rheumatic fever, a disease characterised by heart and joint inflammation, can also occur after an untreated strep throat (Cunningham, 2014). A child with PANDAS may not necessarily manifest with a sore, infected throat. At times, the only symptom may be a stomach ache, a rash or recurrent impetigo, or a persistent sinus or ear infection (O'Hara, 2015). Comprehensive testing, with throat, nasal, ear, and perianal swabs, as well as blood antibody titres against strep antibodies, is recommended, and a viral and bacterial panel is also advisable (Song, 2017). In PANDAS, GABHS antibodies persist for several years after the streptococcal infection occurs (Nicolini et al., 2015). Although strep antibody titres may not always be elevated, this does not exclude a diagnosis of PANDAS (Cooperstock, Swedo, Pasternack, & Murphy, 2017).

My Kid is Not Crazy: A search for hope in the face of misdiagnosis from 4 The Kids Films on Vimeo.

Pathophysiology

The proposed theory for PANS and PANDAS postulates that serum antibodies produced against infectious and non-infectious agents cross the blood-brain barrier (BBB) and cross-react with neuronal antigens (Pearlman, Vora, Marquis, Najjar, & Dudley, 2014). These antibodies then elicit injury and cause dysregulation to basal ganglia functions producing a variety of neurological and psychiatric manifestations (O'Hara, 2015; Pearlman et al., 2014). Anti-neuronal antibodies produced include anti-lysoganglioside, anti-tubulin, and anti- dopamine D1 and D2 receptor antibodies (Cunningham, 2014). Their effects on the brain include alterations to the enzyme tyrosine hydroxylase, resulting in increased synthesis of dopamine (O'Hara, 2015). In addition, dopaminergic and glutamatergic transmission and regulation are affected due to an increase in receptor sensitivity caused by antibody stimulation (O'Hara, 2015). Increased dopamine and glutamate in the basal ganglia may be responsible for the overstimulation and the many psychiatric symptoms associated with PANDAS.

The autoimmune pathophysiology of PANS and PANDAS may result not only from the adverse effects of neuronal antibodies but also from the promotion of inflammatory mediators such as neuroactive cytokines (Calaprice et al., 2017). A role for inflammatory mediators in psychiatric illness has been identified in both children and adults (Baumeister, Russell, Pariante, & Mondelli, 2014; Mitchell & Goldstein, 2014). In addition to their direct action in certain areas of the brain, inflammatory mediators in PANDAS/ PANS have also been implicated in a breach of the BBB by inducing capillaries to expand and allowing the tissues to become more permeable (Calaprice et al., 2017). When this occurs, it makes the BBB vulnerable to the entry of pathogens, permitting neuroactive antibodies to reach neuronal tissue (Calaprice et al, 2017). Of note, research has demonstrated neuroinflammation within the neurocircuitry and pathophysiology of OCD (Attwells et al., 2017; Giedd, Rapoport, Garvey, Perlmutter, & Swedo, 2000; Kumar, Williams, & Chugani, 2014).

Neurons connecting to the basal ganglia affect motor function, emotion, behaviour, procedural learning, cognition, and sensory issues. Neurological and psychiatric manifestations include: OCD, mood lability, depression, mania, irritability, sleep disorders, anxiety (frequently presenting as generalised anxiety or age-inappropriate separation anxiety), rage, developmental regression, hypersexuality, hyperactivity, inattentiveness, oppositional behaviours, obsessive thoughts, checking behaviours, poor muscle control or coordination, new-onset bedwetting, handwriting changes, clumsiness, tics, choreiform movements, cognitive impairment (e.g., slow processing, poor memory, specific sensory learning deficits, particularly in maths and tasks involving calculation), sensitivity to light, sounds, tastes, smells and textures ( PANDAS Physicians Network, 2017). In addition, the PANS/PANDAS child may exhibit a fear of vomiting or of being poisoned or contaminated (O'Hara, 2015). This often leads to difficulties with daily activities such as eating, going to the toilet, going in a car, and dressing. Tics can include uncontrollable movements such as eye-blinking, hair twirling, lip smacking or shoulder shrugging, or automatic noises such as throat clearing, grunting, or saying certain words repeatedly ( PANDAS Physicians Network, 2017).

The impact of PANDAS/ PANS is further exacerbated by certain individual vulnerabilities such as a family history of autoimmune disease, a compromised immune system, impaired detoxification pathways and pyrrole disorder, to name a few.

Due to the nature of a long-standing infection, individuals with PANDAS/ PANS will often present with other issues that require attention. An overactive immune system and persistent infection as seen in children with PANDAS/ PANS exerts an increasing strain on the stress response and the hypothalamic-pituitary-adrenal (HPA) axis (Gruner & Sarris, 2014; Silverman & Sternberg, 2012). Children with PANDAS/ PANS will often have increased stress hormone levels further exacerbating the condition; increase in the stress hormone cortisol, and persistent inflammatory cytokine release, will in turn affect sleep and mood via disruption to serotonin production in the brain (Gruner & Sarris, 2014; Savitz et al., 2015). As this neurotransmitter exerts a modulatory effect on dopamine, lower levels of brain serotonin further exacerbate the effects of dopamine dysregulation in neuronal circuits. Continued disruption in HPA-axis function due to ongoing infection can eventually lead to underproduction of cortisol and other stress hormones (Gruner & Sarris, 2014). This can result in poor stress tolerance, fatigue, sleep issues, and increased susceptibility to other infections (Gruner & Sarris, 2014).

Treatment

Treatment of PANDAS/ PANS requires a multi-pronged approach where a number of modalities are employed in order to address the cause (or causes) and resolve symptoms. Comprehensive treatment delivered by a team of specialists (including paediatric neurologists and psychiatrists, psychotherapists, occupational therapist and naturopath/nutritionist, dependent on the severity of the case) will give the PANDAS/ PANS child the best chance of remission. Generally, the clinical management and treatment of PANDAS/ PANS will comprise behavioural and pharmacological interventions that include antibiotic therapy (often for a period of months or years), immunomodulatory and/or immunosuppressive therapy, psychotropic medication, cognitive behavioural therapy, and family therapy (Thienemann et al., 2017). However, as functional medicine practitioner and paediatrician Elisa Song (2017) has noted, while psychotropic medications may be needed during crises, they are a bandaid solution and are often not effective until the underlying causes are addressed. Most children who undergo treatment show overall improvement over months and years, although relapses may still occur after long periods of remission (Cooperstock et al., 2017).

The focus of treatment should be on each individual child and not a protocol, as symptom presentations differ. Within individualized treatment, however, there is a framework that encompasses dealing with any active infection, addressing the underlying inflammation, modulating the immune system, and supporting the child through the process of flare-ups. Additionally, therapies that support brain and central nervous system function and regeneration, modulate the HPA axis, address nutrient deficiencies (as a consequence of disordered eating) and support gut health, as well as other organs and systems affected, are paramount.

Complementary medicine in the treatment of PANDAS/ PANS has been shown to be helpful, with a high use among patients (Calaprice et al., 2017). The most frequently used treatments include dietary modifications (comprising an anti-inflammatory diet), supplements that include probiotics to support the gut microbiome and gut-brain connection (especially important during antibiotic treatment), vitamin D as an immunomodulatory agent, fish oils (or other omega-3 fatty acids), turmeric/curcumin, vitamin C, melatonin and N-acetylcysteine for reducing oxidative stress and inflammation, B vitamins, magnesium, zinc, broccoli sprout powder and glycine to improve detoxification pathways, and CoQ10, acetyl-carnitine and ribose to address mitochondrial dysfunction (Calaprice et al., 2017; O'Hara, 2015). Further to the above, other interventions include herbal agents with immunomodulatory and/or immunosuppressive actions to optimise immune function and decrease the autoimmune response (Bradbury & Hartley, 2014).

The prognosis for a child with PANDAS/ PANS depends to a great extent on appropriate diagnosis of the disease and early intervention. It is vital that any child exhibiting symptoms of PANDAS/ PANS be referred for proper and comprehensive testing and appropriate treatment. Only then is recovery possible.

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Insomnia, out-of-control tantrums, separation anxiety, rage, obsessions, disordered eating, paranoia, motor and vocal tics. As a therapist or parent, have you come across a child exhibiting any of these behaviours and wondered if there was more to it than psychosocial, developmental or family dynamic issues at play?

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The summer before entering sixth grade, Sammy, a bright and charming boy who lived on the coast of Maine, suddenly began to exhibit disturbing behavior. He walked and ate with his eyes shut, refused to bathe, burst into fits of rage, slithered against walls, and used his limbs instead of his hands to touch light switches, doorknobs, and faucets.

Sammy's mother, Beth, already coping with the overwhelming responsibility of raising three sons alone, watched helplessly as her middle child descended into madness. Sammy was soon diagnosed with obsessive-compulsive disorder (OCD) and later with Tourette syndrome. Unwilling to accept the doctors' prognoses for lifelong mental illness and repeated hospitalizations, Beth fought to uncover what was causing this decline. Beth's quest took her to the center of the medical community's raging debate about whether OCD and Tourette syndrome can be caused by PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections). With the battle lines firmly drawn, Beth searched until she found two cutting-edge doctors who answered that question with a definitive yes. Together, they cured Sammy. Five years later, he remains symptom free.

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Saving Sammy: A Mother's Fight to Cure Her Son's OCD

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Saving Sammy: A Mother's Fight to Cure Her Son's OCD [Maloney, Beth Alison] on Amazon.com. *FREE* shipping on qualifying offers. Saving Sammy: A Mother's Fight to Cure Her Son's OCD

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Greater Regional Health is a healthcare system located in Creston, Iowa, that is made up of multiple entities. Greater Regional Health has over 500+ employees, to best serve our patients of Southwest Iowa. It has grown to much more than just a hospital.

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Greater Regional offers over 50 services lines that deliver big city expertise, but with a home town feel.

Greater Regional is more than a hospital

RELATIONSHIP WITH

Greater Regional Health is an affiliate partner with UnityPoint Health - Des Moines through both a formal management agreement and a Critical Access Hospital network agreement. This relationship enables Greater Regional to retain its governance structure while taking advantage of greater system-wide resources, clinical platforms, best practices and many other advantages which will benefit the people in in our community. Greater Regional remains locally governed by a Board of Trustees and key administration positions to oversee the day-to-day operations of the hospital and its employees.

Compassion, Ownership, Respect, Integrity

OUR VALUES

We are dedicated to recognizing and serving each individual's specific needs through the delivery of person-centered care.

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We accept responsibility for and understand our actions reflect on ourselves and Greater Regional. We are enthusiastically engaged in providing the highest quality care and service for all in a spirit of loyalty and stewardship.

We acknowledge the unique quality of all individuals recognizing each person's contributions drive the innovative spirit and success of our organization.

We serve and work together in an honest, humble and reliable manner while maintaining the highest ethical and performance standards.

OUR MISSION STATEMENT

Greater Regional Health is committed to providing the highest quality health care and service.

OUR VISION STATEMENT

Greater Regional Health will be the healthcare provider and employer of choice.

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About Us | Greater Regional Health | Southwest Iowa

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Greater Regional Health is a healthcare system located in Creston, Iowa, that is made up of multiple entities. Greater Regional Health has over 500+ employees, to best serve our patients of Southwest Iowa. It has grown to much more than just a hospital.

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The PING (Psychiatry Immunology and Neurology Group) Clinic provides care for children, adolescents, and young adults with complex neurological and psychiatric disorders that occur following an infection or illness. Our team of providers works with a diverse group of specialties to help give our patients comprehensive care.

New patients

If you feel your child should be seen in the PING Clinic, please have your primary care provider send a referral to our clinic. Once you have received your child's appointment, download the intake information form and age-appropriate questionnaire for your child below. Fill these out in advance and bring them to your child's first appointment with us.

Please refer to the following sections on this page:

Conditions we treat

We evaluate and treat the following conditions:

Childhood post-infectious autoimmune encephalopathy (CPAE) or pediatric autoimmune neuropsychiatric disorder (PANS)

Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS)

Neuropsychiatric illnesses associated with autoimmune conditions such as:

Inflammatory bowel disease

Lupus

What are CPAE, PANS, or PANDAS?

Both CPAE and PANS are descriptive names for the same group of conditions. They happen when a child's immune response to an infection causes inflammation in the brain. The inflammation can cause the sudden onset of behavioral, neurological, and personality changes. It's called 'sudden onset' because the changes occur quickly, usually within 2 to 3 days. These conditions are diagnosed in children aged 3 years to puberty. These sudden symptoms include one or both of the following:

Obsessive-compulsive disorder (OCD)

Avoidant restrictive food intake disorder (ARFID)

PANDAS is a subset of PANS where symptoms are triggered by a streptococcus infection, like strep throat. Children who have had a recent infection or illness are at the highest risk for any of these 3 conditions - CPAE, PANS, or PANDAS. To be diagnosed with CPAE, PANS, or PANDAS, a child must have either OCD or ARFID, and 2 or more of the following neuropsychiatric symptoms:

Anxiety (often social or separation)

Behavioral or developmental regression (for example, baby talk)

Change in school performance, ADHD-like symptoms, memory, and cognitive changes

Depression or mood swings

Irritability or aggression

Sensory or motor changes (for example, new tics)

Trouble sleeping, bedwetting, or urinary accidents

Our services

We focus on helping patients, their families, and physicians understand these complex conditions. Our team provides:

Comprehensive evaluation

Consultation

Ongoing care

Treatments that incorporate medical and behavioral health including:

Managing medications

Preventing and treating infection and inflammation

Treating neuropsychiatric symptoms and providing family support with psychotherapy

As part of their evaluation or treatment your child may see providers from one or more of these specialties:

Research

We focus on improving diagnosis and treatment for patients with neuroinflammatory conditions. Our program includes ongoing clinical, epidemiological, and scientific research. We are part of the PANS Research Network as well as the CPAE Clinics of Excellence Network.

Referrals and appointments

If your child is a returning patient: You may use myD-H to communicate securely with your child's providers, request or change appointments, review your child's medical record, and more.

If you are a health care professional: To make sure the child you are referring is seen in the PING Clinic, please make sure you include PING as part of the referral.

Our team
Pediatric Immunology and Neurology Group (PING) Clinic team

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pediatric immunology and neurology group

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avoidant restrictive food intake disorder

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PING (Psychiatry Immunology and Neurology Group)

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The PING (Psychiatry Immunology and Neurology Group) Clinic provides care for children, adolescents, and young adults with complex neurological and psychiatric disorders that occur following an infection or illness. Our team of providers works with a diverse group of specialties to help give our patients comprehensive care.

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Address

1 Children's Way
Little Rock, AR 72202

Contact Information

General Information and Appointments

501-364-6891

Fax Number

501-686-5975

Hours Vary

Appointments are made after information is collected via e-mail by our clinic coordinator. Please email cpaeclinic@uams.eduto begin the appointment process.

After Hours

If you are in need of urgent or emergency care, call 911 or go to your nearest emergency department at your local hospital.

If you are sick or have a minor injury and need to talk to someone right away, you can access UAMS HealthNow for a video visit with a UAMS Health provider 24 hours a day, 7 days a week.

Contents

About Childhood Post-infectious Autoimmune Encephalopathy (CPAE) Center of Excellence

The Childhood Post-infectious Autoimmune Encephalopathy (CPAE) Center of Excellence at Arkansas Children's Hospital, developed in partnership with UAMS and in cooperation with the NIH/NIMH utilizes a multidisciplinary approach to implement an integrated model of basic science and clinical research, clinical care and teaching to address a spectrum of neuropsychiatric disorders that are often misdiagnosed, underdiagnosed or undiagnosed in children.

Post-infectious Autoimmune Encephalopathy (PAE) is a condition where an infection triggers an autoimmune reaction that targets the brain, leading to changes in neurologic function, mood and behavior. PAE includes disorders such as PANS (Pediatric Acute-onset Neuropsychiatric Syndrome), PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection).

The CPAE Center of Excellence has three goals:

To deliver multidisciplinary, state-of-the-art care to children who experience behavioral and neurological changes after an infection.

To investigate the causes of Postinfectious Autoimmune Encephalopathy.

To find new treatments to improve outcomes and eventually cure children with Postinfectious Autoimmune Encephalopathy.

Affiliation

Arkansas Children's Hospital Neurosciences Center

Appointment Information

Appointments are made after information is collected via e-mail by our clinic coordinator. Please e-mail cpaeclinic@uams.edu to begin the appointment process.

What to Expect at Your Appointment

Clinical services are provided at Arkansas Children's Hospital and children treated at the center will be offered a multidisciplinary evaluation, recommendations to your primary care provider and care team, and ongoing support to you and your primary care provider.

Patients are not offered medical interventions or treatments at the time of their visit. We are not able to offer acute inpatient psychiatric care or transportation to/from our clinic. We are also unable to guarantee insurance coverage.

Arkansas Children's MyChart

Now you can manage your child's medical information and connect with your Arkansas Children's medical team anytime online with MyChart. MyChart lets you access every aspect of your child's care whenever you need it. No more waiting for a call back to get answers; now, you can find the information you need in minutes.

MyChart at ACH enables you to:

Manage your child's health information

Communicate with your child's doctor

Access test results faster

Manage appointments

Request prescription refills

Providers at Childhood Post-infectious Autoimmune Encephalopathy (CPAE) Center of Excellence

Tiffany A. Howell, Ph.D. Psychologist

Veronica M. Raney, M.D. Psychiatrist

Aravindhan Veerapandiyan, M.D. Pediatric Neurologist

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Childhood Post-infectious Autoimmune Encephalopathy (CPAE) Center of Excellence | UAMS Health

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1 Children's Way Little Rock, AR 72202 General Information and Appointments 501-364-6891 Fax Number 501-686-5975 Appointments are made after information is collected via e-mail by our clinic coordinator. Please email cpaeclinic@uams.edu to begin the appointment process. If you are in need of urgent or emergency care, call 911 or go to your nearest emergency department at your local hospital.

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Please note: A referral from pediatrician or family practitioner required

Located on the campus of Cardon Children's Medical Center in Mesa, the CPAE Clinic is a program of Banner Children's Specialists. Here, pediatricians, pediatric neurologists and pediatric neuropsychologist collaborate with their Tucson-based clinical and research colleagues at Diamond Children's Medical Center and the University of Arizona Steele Children's Research Center.

Acute-onset neuropsychiatric disorders in children often go misdiagnosed or undiagnosed. The Children's Postinfectious Autoimmune Encephalopathy (CPAE) Clinic gives pediatric patients the expert care they need when an infection-induced autoimmune reaction targets the brain. The resulting changes in neurologic function, mood and behavior require swift, specialized care.

Conditions that may lead to neurologic autoimmune reactions include:

Group A beta hemolytic strep

Other infectious triggers

Symptoms of CPAE include acute sudden onset of:

Obsessive-compulsive disorder

Restrictive eating

Separation anxiety

Enuresis

Tics (motor and phonic)

Sensory sensitivities

Irritability and aggression

Decline in academic performance

Changes in handwriting

Difficulty with mathematics

Treatment for CPAE is tailored to the individual needs of each patient. Depending on the root cause and symptoms present, treatment may include:

Cognitive behavior therapy

Underlying infection treatment

Immunomodulation

Referral for appropriate psychiatric care

View/Print a fact sheet about this clinic

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Banner Children's Autoimmune Encephalopathy Clinic in Mesa, AZ

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Please note: A referral from pediatrician or family practitioner required Located on the campus of Cardon Children's Medical Center in Mesa, the CPAE Clinic is a program of Banner Children's Specialists. Here, pediatricians, pediatric neurologists and pediatric neuropsychologist collaborate with their Tucson-based clinical and research colleagues at Diamond Children's Medical Center and the University of Arizona Steele Children's Research Center.

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The Children's Postinfectious Autoimmune Encephalopathy (CPAE) Center of Excellence at the University of Arizona Steele Children's Research Center, developed in partnership with Banner-University Medicine and in cooperation with the NIH/NIMH is the first in the U.S. to implement an integrated model of basic science and clinical research, clinical care and teaching to address a spectrum of neuropsychiatric disorders that are often misdiagnosed, underdiagnosed or undiagnosed in children.

Postinfectious Autoimmune Encephalopathy(PAE)is a condition where an infection triggers an autoimmune reaction that targets the brain, leading to changes in neurologic function, mood and behavior. PAE includes disorders such as PANS (Pediatric Acute-onset Neuropsychiatric Syndrome), PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection) and Sydenham chorea.

The CPAE Center of Excellence has three goals:

1. To deliver multidisciplinary, state-of-the-art care to children who experience behavioral and neurological changes after an infection.

2. To investigate the causes of Postinfectious Autoimmune Encephalopathy (PAE).

3. To find new treatments to improve outcomes and eventually cure children with Postinfectious Autoimmune Encephalopathy (PAE).

Basic science and translational research of PAE is conducted at the UArizona Steele Children's Research Center, a world-renowned research center with cutting-edge researchers studying inflammation, microbiome, and the genetics of complex diseases.

Clinical services are provided at Banner - Diamond Children's Multispecialty Clinic, and children treated at the center will be offered enrollment in clinical research trials led by UArizona Steele Children's Research Center physician-researchers.

Newsletters
Fall 2021
Panopto Education Series Videos
Navigating CPAE - How to Make an Appointment Childhood Post-infectious Autoimmune Encephalitis_PANDA Problems Alterationsin Expected Development Introduction to the Immune System Pre-visit Testing Evaluation Psychiatric Medical Treatment of OCD and Anxiety in PANS PANDAS From Controversy to a Clinically Useful Classification Approach to PANS/PANDAS Assessment of Family Accommodations and Secondary Gains in CPAE/PANS/Pandas Challenges faced by families of children with CPAE/PANS/PANDAS

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Welcome to the Children's Postinfectious Autoimmune Encephalopathy (CPAE) Center of Excellence

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The Children's Postinfectious Autoimmune Encephalopathy (CPAE) Center of Excellence at the University of Arizona Steele Children's Research Center, developed in partnership with Banner-University Medicine and in cooperation with the NIH/NIMH is the first in the U.S.

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The Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Program at the Heartwood Program is dedicated to providing consultation services to children, adolescents, families, and clinicians to provide clarity and direction on the evaluation, diagnosis and treatment of PANDAS/PANS.

Our multidisciplinary team of professionals, led by Dr. Susan Swedo, the founder of and worldwide expert on the topic of PANDAS and PANS, brings together a broad range of skills, knowledge, and sensitivity to provide evaluations, diagnostic clarity, and treatment recommendations for children and adolescents up to age 18. At the end of the visit, our team discusses the results of the evaluation with the patient and their family. The team then communicates the recommendations to the primary treating provider and remains available for ongoing consultation and guidance. Clients who have a diagnosis of PANDAS or PANS will be offered ongoing follow-up consultation services.

For any questions, call us at (301)-970-4099.

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PANDAS/PANS - PANDAS/PANS Consultation Program

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The Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Program at the Heartwood Program is dedicated to providing consultation services to children, adolescents, families, and clinicians to provide clarity and direction on the evaluation, diagnosis and treatment of PANDAS/PANS.

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What Is PANDAS?

PANDAS, or P.A.N.D.A.S., is short for Pediatric AutoImmune Neuropsychiatric Disorders Associated with Streptococcal Infections. PANDAS is hypothesized to be caused by strep bacteria, which can hide from a child’s immune system by mimicking healthy cells in the skin, heart, joints, and brain tissue. Children with PANDAS experience a sudden onset or worsening of tics and/or Obsessive-Compulsive Disorder (OCD). While many children may experience strep throat, OCD, or tics, PANDAS is diagnosed when there is a close relationship found between the onset/severity of these symptoms and a streptococcal infection.

Clinical Approach

Vision

To improve understanding of the etiology and most effective treatments of pediatric neuropsychiatric immune conditions through our integrated clinic and research program.

Mission Statement

To provide high quality, comprehensive and wholistic care of children with suspected pediatric neuropsychiatric immune conditions.

How to Request an Appointment

To request an appointment, please call 617-724-0198.

What Is Involved with an Appointment?

For the health and safety of our patients and staff, appointments are currently taking place via telehealth during the COVID-19 pandemic.

Everything Parents Need to Know about PANDAS

Learn about PANDAS' causes, symptoms, and treatments and get your most frequently asked questions answered. Learn more.

Meet the Team

Kyle Williams, MD, PhD

Dr. Williams is the Director of the Pediatric Neuropsychiatry and Immunology Program in the OCD and Related Disorders Program at Massachusetts General Hospital, and Instructor in Psychiatry at Harvard Medical School. Dr. Williams received his M.D. from the University of Minnesota Medical School, and completed training in Adult and Child Psychiatry at the Yale Child Study Center as part of the Solnit Integrated Program in Child and Adolescent Psychiatry.

Sarah O'Dor, PhD

Dr. O’Dor is the Director of Research at the PNIP and a Licensed Clinical Psychologist. She attended Boston College for her undergraduate studies and received her Ph.D. in clinical psychology from Northwestern University Feinberg School of Medicine in Chicago. She completed her clinical internship and two-year postdoctoral fellowship at MGH/Harvard Medical School specializing in child and adolescent psychotherapy and neuropsychological assessment.

Mark Pasternack, MD

Dr. Pasternack is the unit chief of Pediatric Infectious Disease at MassGeneral Hospital for Children.

PNIP Research Program

We provide opportunities for both children and adolescents with and without PANDAS to participate in research.

Learn more

Patient Resources

PANDAS Network

PANDAS Physician's Network

International OCD Foundation

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Pediatric Neuropsychiatry and Immunology Program (PNIP)

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We are clinicians and staff committed to helping children and families dealing with P.A.N.D.A.S. (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection) through clinical practice and research projects.

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2. American Family Children's Hospital

3. Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) Clinic

1675 Highland Ave. / Madison, WI

(608) 888-8447

Monday 8:00am-5:00pm

Tuesday 8:00am-5:00pm

Wednesday 8:00am-5:00pm

Thursday 8:00am-5:00pm

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American Family Children's HospitalPediatric Acute Onset Neuropsychiatric Syndrome (PANS) Clinic

1675 Highland Ave. / Madison, WI

View hours, services and more

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Serving more than 600,000 patients each year in the Upper Midwest and beyond at seven hospitals and more than 80 outpatient sites.

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We are the sole fundraising entity for Lucile Packard Children's Hospital Stanford and the child health programs at Stanford University School of Medicine. Join us in supporting care, comfort, and cures.

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Home | Lucile Packard Foundation for Children's Health

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We are the sole fundraising entity for Lucile Packard Children's Hospital Stanford and the child health programs at Stanford University School of Medicine. Join us in supporting care, comfort, and cures.

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PANS: Pediatric Acute-onset Neuropsychiatric Syndrome
Department of Pediatrics - Division of Allergy, Immunology & Rheumatology

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Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinical diagnosis given to children who have a dramatic – sometimes overnight – onset of neuropsychiatric symptoms including obsessions/compulsions or food restriction. They are often diagnosed with obsessive-compulsive disorder (OCD) or an eating disorder, but the sudden onset of symptoms separates PANS from these other disorders. In addition, they may have symptoms of depression, irritability, anxiety, and have difficulty with schoolwork. The cause of PANS is unknown in most cases but is thought to be triggered by infections, metabolic disturbances, and other inflammatory reactions.

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The Forgotten Children- A UK PANS/PANDAS Documentary

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My Kid is Not Crazy: a search for hope in the face of misdiagnosis-  cinema release (2018)

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ASPIRE Lecture- PANS PANDAS - Susan Swedo, MD & Gabriella True for Comitato Italiano Genitori Pandas

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Town Hall: PANDAS/PANS in Partnership with Pandas Physicians Network (PPN)

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New England PANS/PANDAS Association, Connecticut Chapter Conference. Dr. Nancy O’Hara, Presentation

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Dr Swedo PANDAS/PANS Standards of Care Summit October 4, 2018

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November 2013 - Dr. Latimer, PANDAS: One SIze Does Not Fit All

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SANE Sweden International PANS Conference 2019 Pooling Knowledge – Moving Forward

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PANS / PANDAS OVERVIEW with Dr Rosario R. Trifiletti, MD, PhD

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PANS and PANDAS in ASD - Nancy O'Hara, MD

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1. Saskatoon PANS PANDAS Conference Dr. Susan Swedo Presentation

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New England PANS/PANDAS Association, Connecticut Chapter Conference. Dr. Leventhal, Presentation

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Presentations focused on educating physicians, medical professionals, and the public about PANDAS and PANS.

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What is PANDAS?

PANDAS stands for pediatric autoimmune neuropsychiatric disorders associated with streptococcus. The syndrome involves sudden and often major changes in personality, behavior, and movement in children following an infection involving Streptococcus pyogenes (streptococcal-Ainfection).

Strep infections can be mild, causing nothing more than a minor skin infection or sore throat. On the other hand, they can cause severe strep throat, scarlet fever, and other illnesses. Strep is found inside the throat and on the surface of the skin. You contract it when an infected person coughs or sneezes and you breathe in the droplets or touch contaminated surfaces, and then touch your face.

Most people with a strep infection make a full recovery. However, some children develop sudden physical and psychiatric symptoms a few weeks after infection. Once they start, these symptoms tend to rapidly get worse.

Continue reading to learn more about the symptoms of PANDAS, how it's treated, and where you can turn for help.

The symptoms of PANDAS start suddenly, about four to six weeks after a strep infection. They include behaviors similar to obsessive-compulsive disorder (OCD) and Tourette syndrome. These symptoms can interfere with schooling and quickly become debilitating. Symptoms worsen and reach their peak usually within two to three days, unlike other childhood psychiatric illnesses that develop more gradually.

Psychological symptoms may include:

obsessive, compulsive, and repetitive behaviors

separation anxiety, fear, and panic attacks

incessant screaming, irritability, and frequent mood changes

emotional and developmental regression

visual or auditory hallucinations

depression and suicidal thoughts

Physical symptoms may include:

tics and unusual movements

sensitivities to light, sound, and touch

deterioration of small motor skills or poor handwriting

hyperactivity or an inability to focus

memory problems

trouble sleeping

refusing to eat, which can lead to weight loss

joint pain

frequent urination and bedwetting

near catatonic state

Children with PANDAS don't always have all of these symptoms, but they generally have a mix of several physical and psychiatric symptoms.

The exact cause of PANDAS is the subject of ongoing research.

One theory proposes that it may be due to a faulty immune response to strep infection. Strep bacteria are particularly good at hiding from the immune system. They mask themselves with molecules that look similar to normal molecules found in the body.

The immune system eventually catches on to the strep bacteria and begins producing antibodies. However, the disguise continues to confuse the antibodies. As a result, the antibodies attack the body's own tissues. Antibodies targeting a particular area of the brain, the basal ganglia, may cause the neuropsychiatric symptoms of PANDAS.

The same set of symptoms can be brought on by infections that don't involve strep bacteria. When that's the case, it's called pediatric acute-onset neuropsychiatric syndrome (PANS).

PANDAS is most likely to develop in children between 3 and 12 years old who've had a strep infection within the last four to six weeks.

Some other possible risk factors include a genetic predisposition and recurrent infections.

Your child is more likely to get a strep infection in late fall and early spring, especially when they're in close quarters with large groups of people. To help prevent strep infection, teach your child not to share eating utensils or drinking glasses, and to wash their hands often. They should also avoid touching their eyes and face whenever possible.

If your child is showing unusual symptoms after an infection of any kind, make an appointment with your pediatrician right away. It might be helpful to keep a journal detailing these symptoms, including when they started and how they're affecting your child's life. Bring this information, along with a list of any prescription or over-the-counter medications your child takes or has recently taken, when you visit the doctor. Be sure to report any infections or illnesses that have been going around at school or home.

To diagnose a strep infection, your pediatrician may take a throat culture or run a blood test. However, there are no laboratory or neurological tests to diagnose PANDAS. Instead, your doctor may want to perform a variety of blood and urine tests to rule out some other childhood ailments.

A diagnosis of PANDAS requires a careful medical history and physical examination. The criteria for diagnosis are:

being between three years old and puberty

sudden onset or worsening of already existing symptoms, with symptoms becoming more severe for periods of time

presence of obsessive-compulsive behaviors, tic disorder, or both

evidence of other neuropsychiatric symptoms, such as hyperactivity, mood changes, developmental regression, or anxiety

previous or current strep-A infection, confirmed by a throat culture or blood test

Treating PANDAS involves addressing both the physical and psychiatric symptoms. To start, your pediatrician will focus on making sure the strep infection is completely gone. You'll also need to work with a licensed mental health professional familiar with OCD and PANDAS.

Treating the strep infection

Strep infections are treated with antibiotics. Most strep infections are successfully treated with a single course of antibiotics. Some of the antibiotics used to treat strep include:

You should also consider having other family members tested for strep because it's possible to carry the bacteria even though you have no symptoms. To help avoid re-infection, replace your child's toothbrush right away and again when they finish their full course of antibiotics.

Treating psychological symptoms

Psychiatric symptoms may start to improve with antibiotics, but they'll likely still need to be addressed separately. OCD and other psychiatric symptoms are generally treated with cognitive behavioral therapy.

OCD also usually responds well to selective serotonin reuptake inhibitors, a type of antidepressant. Some common ones include:

These medications will be prescribed in small doses to start. They can be slowly increased if necessary.

Other treatments are controversial and must be decided on a case-by-case basis. Some doctors may prescribe corticosteroids, such as prednisone, to improve symptoms of OCD. However, steroids can make tics even . In addition, when steroids do work, they can only be used for a short period. At this point in time, steroids are not routinely recommended for the treatment of PANDAS.

Some severe cases of PANDAS might not respond to medications and therapy. If this happens, a blood plasma exchange to remove the faulty antibodies from their blood is sometimes recommended. Your pediatrician may also recommend intravenous immunoglobulin therapy. This procedure uses healthy donor blood plasma products to help boost your child's immune system. While some clinicians report success with these treatments, there are no studies confirming that they work.

Symptoms of PANDAS can leave your child unable to function at school or in social situations. Untreated, symptoms of PANDAS may continue to worsen and can result in permanent cognitive damage. For some children, PANDAS can become a chronic autoimmune condition.

Having a child with PANDAS can be extremely stressful because it tends to come on without warning. Over the course of a few days, you might notice dramatic behavioral changes with no apparent cause. Adding to this challenge is the fact that there is no one test for PANDAS, though diagnostic criteria have been developed. It's important to make sure these criteria are met before diagnosing PANDAS.

If you feel overwhelmed, consider these resources:

Your child may also need extra help at school. Talk to their teacher or school administrators about the diagnosis, what it means, and how you can all work together in the best interests of your child.

PANDAS wasn't identified until 1998, so there aren't any long-term studies of children with PANDAS. However, this doesn't mean your child can't get better.

Some children improve quickly after starting antibiotics, though symptoms may return if they get a new strep infection. Most recover without significant long-term symptoms. For others, it can become an ongoing problem requiring periodic use of antibiotics to control infections that may cause flare-ups.

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PANDAS Syndrome: Symptoms, Causes, Diagnosis, and Treatment

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What is PANDAS? PANDAS stands for pediatric autoimmune neuropsychiatric disorders associated with streptococcus. The syndrome involves sudden and often major changes in personality, behavior, and movement in children following an infection involving Streptococcus pyogenes (streptococcal-Ainfection). Strep infections can be mild, causing nothing more than a minor skin infection or sore throat.

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how to stop obsessive compulsive disorder

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Pandas, the condition that suddenly changes a child's behaviour

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A sudden and dramatic change in their son's behaviour led Katy and Ben Chandler on a two-year journey to a diagnosis of Pandas - the start of a long, hard road to recovery.

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PANDAS syndrome: Symptoms, causes, treatment, and more

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PANDAS syndrome is a group of mental health conditions that suddenly appear in a child after a strep infection. Learn about the causes, symptoms, and treatment.

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Has your child suddenly developed intense OCD and anxiety? It may be a sign of pediatric acute-onset neuropsychiatric syndrome (PANS) or pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS).

What is PANS or PANDAS?

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a childhood condition characterized by the sudden onset of obsessive-compulsive symptoms (OCD) and/or eating restrictions following a bacterial or viral infection, including COVID-19. These sudden changes often appear in combination with behavioral and neurological changes such as new fears, anxiety, depression, tics, changes in temperament, and sensory sensitivity that causes increased urination or sleep disturbances. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is a subset of PANS, but is linked to a strep bacterial infection.

Following a normal childhood illness such as a sore throat or a stomachache, a child with PANS or PANDAS may suddenly (what seems like overnight) start exhibiting signs of psychological distress. They might wash their hands excessively, suffer from fears they never had before, worry about feeling sick, refuse to eat food, and begin struggling in school. Your child may feel hopeless, anxious, be on edge, or feel like they're on the verge of a breakdown because of the constant obsessive thoughts or tics.

Scientists believe that 1 in 200 children suffer from PANS or PANDAS, with an average age of onset between 4 and 10 years of age. PANS/PANDAS is an "episodic illness", meaning symptoms can go away for a while after an infection is treated, but they can come back again, in what is called a flare-up or relapse of the disorder. These relapses usually occur when your child is exposed to another virus, another case of strep throat, or an environmental substance such as mold or allergens. Symptoms may increase in severity with every episode, or even last longer than the previous episode. With some children, their symptoms last for months, or even years, and can progressively get worse over time.

While it can be extremely distressing as a parent to witness your child suffer, it doesn't mean that they will be impacted by PANS or PANDAS forever. A flare up does not last forever, and symptoms do eventually subside for most patients. In fact, some studies suggest that about 95% of kids will outgrow PANS or PANDAS by adolescence or young adulthood when their immune systems fully mature. In the meantime, there are steps you can take to help ease your child's suffering.

Signs and symptoms of PANS and PANDAS

PANS/PANDAS is characterized by sudden onset of OCD and/or severe eating restrictions (refusing to eat certain or all foods), along with at least two other cognitive, behavioral, or neurological symptoms, such as:

Anxiety such as excessive worry, irrational fears, separation anxiety, or panic attacks.

Behavioral or developmental deterioration, such as having temper tantrums or a sudden loss of age-appropriate language skills.

Emotional distress such as depression, suicide ideation, inappropriate emotional reactions, or dramatic mood swings.

Irritability including aggression, lashing out, or defiance.

Sudden decrease in school performance, along with symptoms of ADHD or a decline in math capability.

Motor or sensory abnormalities such as tics, heightened sensitivity, and handwriting decline.

Sleep disturbances such as night terrors, trouble falling or staying asleep, or new issues with bedwetting.

Frequent urge to urinate, without the presence of a urinary tract infection.

[Read: Obsessive-Compulsive Disorder (OCD)]
The OCD that kids experience with PANS tends to differ from typical OCD symptoms as the obsessions or compulsions come on suddenly, usually over a day or two after onset of the initial infection. Typical OCD, on the other hand, usually develops more slowly over a period of time.

Causes and diagnosis

Some children can have 10 or more separate strep infections in their life and never suffer any adverse effects, while another child may get their first or second infection and end up experiencing all of the negative symptoms of PANDAS. Experts believe that some kids have a genetic vulnerability that makes them more likely to suffer from PANS or PANDAS. An infection leads to an abnormal immune system response that attacks certain parts of the brain, causing inflammation and an abrupt onset of symptoms.

PANS can be triggered by one or more infections, like the flu, Lyme disease, mycoplasma (a type of walking pneumonia), chicken pox, upper respiratory infections, and an unending list of viruses, including COVID-19 and its variants.

Diagnosing PANS/PANDAS

Getting a diagnosis of PANS or PANDAS can be difficult as the effect of an inflamed immune system on the brain is not always well understood by some physicians. Since there is currently no specific test to identify PANS or PANDAS, the condition can be frequently misdiagnosed. Being an advocate for your child is a necessity when pursuing a diagnosis of PANS/PANDAS.

If your child has a strep infection, your doctor will likely start a course of antibiotics. They may also ask for a strep throat culture or blood work that could show an immune response or another type of infection, such as Lyme disease, Epstein Barr virus, or a Coxsackievirus.

With the outbreak of the COVID-19 pandemic, however, more people have suffered mood changes, muscular dysfunction, and psychological distress as side effects of infection. This has validated what many parents already know about PANS and how it can affect a child.
[Read: Long COVID: Symptoms and Help for COVID Long Haulers]
The widespread psychological reactions to coronavirus infection have also led to an increase into research into why pathogens can affect the brain of some people but not others, which in future will hopefully make PANS or PANDAS easier to diagnose.

Helping a child with PANS/PANDAS

When your child is experiencing OCD or anxiety symptoms of PANS or PANDAS, the whole household can feel the effects. Everyone may feel that their lives have been interrupted and also feel the need to adapt to your child's OCD rituals, whether it be their hand washing, fears about germs, or intrusive thoughts, for example. As a parent, though, it's important to be caring and understanding, and not overly criticize or blame your child, which may only lead to increased anxiety and exacerbate the symptoms of OCD.

Try to empathize with what your child is feeling, reassure them that they will get better, and encourage them to face their fears and deal with their emotions. The message you want to send is: "I know you're not feeling well; I know you are scared and anxious. But I'm going to be here to help you get through this."

Studies have shown that supportive parents, rather than overly critical parents, can help their children reduce anxiety symptoms. However, it's important to know that you cannot completely prevent a child from experiencing OCD or anxiety symptoms, either. Your child will need to learn how to deal with their worries and anxieties. For example, if your child has separation anxiety at night and you decide to sleep with them, you're giving in to their fears rather than enabling your child to develop the necessary coping skills.

Repeated exposure to their fears in a controlled way can, in fact, have some beneficial reduction in the stress and anxiety they feel. Exposure and Response Prevention (ERP) therapy is commonly used to reduce OCD symptoms. It works by gradually exposing your child to the fears that trigger their OCD while they learn to resist the urge to complete the compulsive rituals. By starting with a situation that only causes mild anxiety, your child can learn to tolerate their fear before moving on to another situation that causes them slightly more anxiety, and so on.
[Read: Learn to Resist OCD Compulsions]
The following tips can also help you and your child manage the stress and anxiety that comes with PANS/PANDAS either during the initial illness or a flare-up.

Tip 1: Talk to your child about how they're feeling

One of the most effective ways to calm down when you're stressed is to talk face-to-face with someone who cares about you. For you as an adult, you may turn to friends, co-workers, or loved ones. Your child will want to turn to you, so make a point of talking with them to understand how they feel.

If, for example, your child is experiencing separation anxiety as part of their OCD-a common response to PANS or PANDAS-talking through what they're afraid of, providing reassurance, and making a plan to deal with their fears can help them react more positively. Try asking open-ended questions like: "How do you feel today?" instead of a question like "Are you feeling anxious?" that requires only a "Yes" or "No" answer. Such close-ended questions tend to feed the cycle of anxiety and stress that your child is feeling.

Additionally, let your child know that you are proud of them for facing their fears, obsessions and compulsions, and let them know that the more they deal with facing those fears, the less they will have anxiety about them.

Focus on the positive

Having your child see the positives in their life can be really beneficial for the way the child feels about themselves and how they deal with their illness. Encourage your child to take a few minutes each day to focus on the positive aspects of their life, things they're grateful for-no matter how small. Also, having your child read about how other kids have overcome adversities can make them feel less alone in their symptoms and illness.

Tip 2: Self-soothe with deep breathing

Breathing matters! During an anxious time, children are less likely than adults to be able to breathe properly. Kids need to learn how to breathe through their stress. When your child is stressed out, their body goes into "fight or flight" mode, their heart races, and their breath becomes shallow (almost feeling like they're not getting enough air). Deep breathing can help your child feel calmer and reduce their anxiety.

Using bubbles can be a fun way to help kids learn how to deep breathe. To blow bubbles they need to use their diaphragm, and the diaphragm is the part of the body that has to be used in deep breathing. Have your child practice taking in a long, deep breath through their nose, holding the air in their belly for a count of two, and then slowly blowing bubbles as big as they can. Then repeat the process over until the anxiety has passed. This can help kids learn to use breath to quickly soothe themselves.
[Listen: Deep Breathing Meditation]
The 5-5-10 method of breathing can also be helpful. This is a method where you take a breath for 5 seconds, hold it in for 5 seconds, and then release the breath through your mouth for 10 seconds. Or take a "snake breath" by breathing in and filling your diaphragm and then slowly hissing out the air through your teeth like a snake. Do the breathing exercise along with your child and make a game of who can take the longest to hiss out the air. All of these activities help oxygenate the blood and improve the way the brain responds to stress.

Tip 3: Distract with calming activities

Distraction is a proven method to help people, especially children, cope during a stressful time. Distractions work in that they help divert the child's attention from feeling anxiety and stress so they can be more relaxed. Having your child play a board game with you or complete a puzzle will help them refocus their energy into an activity and forget about the stress they may be feeling.

Other calming activities for children include drawing, painting, listening to music, or playing with a friend.

Tip 4: Encourage exercise

Exercise has long been known to help ease and lessen symptoms of stress, depression, and anxiety in adults, and it is no different for children. Exercise can be effective in that it forces the child to focus more on the actions they are doing-whether it be running, cycling, or playing soccer, for example-instead of the things they are feeling. The break from their obsessions and compulsions can also help a child feel a sense of increased command over their symptoms.

Spending time outside in green spaces can also be a calming, soothing experience for an anxious child. Encourage your child to spend time exercising outdoors or try hiking or walking in a park or woodland together.

Tip 5: Be a good role model

Children are sponges. They soak up experiences around them and mimic the behaviors of those closest to them-including how you as their parent manage stress and anxiety in your own life. By handling stressors in a positive way, you can set a positive example to your child.

Rather than using alcohol or drugs to cope, for example, or flying off the handle when things get stressful, let your child see you manage stress and anxiety in more positive ways by:

Treatment

Antibiotics are the primary treatment in the fight against PANS and PANDAS. If a child has been found to have a strep infection, antibiotics are definitely needed to treat the illness. But be aware that if your child does not have a positive strep test, doctors may be much less likely to prescribe antibiotics, which is where many parents of children who present with PANS symptoms feel like they run into a brick wall.

Antibiotic prophylaxis may also be used to prevent infections from potential illnesses your child could come in contact with that could cause a flare up.

Additional treatments

Steroids can help ease inflammation in a child's brain and also assist in reducing symptoms. However, some children can have a negative response to steroids and become much more aggressive or experience greater severity of tics.

Cognitive Behavior Therapy (CBT) can teach kids better ways to cope with the psychological symptoms of PANS, how to face their fears, and how to calm and relax their mind and body.

Tonsillectomy is an interesting, but controversial, treatment option for PANS and PANDAS. In one study, researchers found that when tonsils are removed, the symptoms go away completely for many patients. However, it was not a controlled study and so some experts consider the evidence too incomplete to determine effectiveness of a tonsillectomy.

Intravenous immunoglobulin (IVIG) , which is a therapeutic exchange of blood plasma, may be used for children who get no relief from the other treatments. IVIG is costly, though, and most insurances do not cover the procedure.

Non-steroidal anti-inflammatory drugs (NSAIDS) like Advil and Motrin are often given to patients because of the anti-inflammatory properties in the drugs.

Supplements

There are also some supplements that may have a positive effect on children with PANS.

Giving the child an Omega 3 fish oil supplement may help to reduce inflammation.

Some studies have shown the use of probiotics may be beneficial as it helps with increasing good gut bacteria, which in turn can have a positive effect on the mind.

Some parents have found that turmeric or curcumin supplements can be beneficial because of their natural anti-inflammatory properties.

Likewise, vitamin D supplements may also have anti-inflammatory properties and have been prescribed to children with auto-immune responses for other issues.

Taking care of yourself

PANS can be very traumatic for families, especially the primary caregiver. Many parents feel neglected by the medical community while their child continues to suffer. Studies show that parents caring for children with PANS often face an extreme burden, especially in severe cases, and are more likely to experience high levels of anxiety.

Left unchecked, the burden of caregiving can take a heavy toll on your mental, emotional, and physical health, even leading to burnout. As your child's primary caregiver, if you neglect your own health and welfare, it will affect not only yourself but also your child and the rest of the family.
[Read: Caregiver Stress and Burnout]
It's imperative you take steps to ease the burden of caregiving and prevent caregiver burnout.

Take a break. Make sure that you have time where you can be calm and alone to collect your thoughts and try to decompress. This could be as simple as taking a walk by yourself or going to the gym, just to get away for a while without the constant reminder of your child's illness.

Practice meditation. Meditating breaks the cycle of stress and allows you to focus on the moment instead of worrying about the past or the future. Try one of HelpGuide's free audio meditations.

Find Support. There are many support groups for parents, caregivers and family members of kids with PANS or PANDAS. Talking to others who are experiencing the same issues can help you to feel less isolated and enable you to access new coping tips.

Start a Journal. Journaling can be a positive and cathartic way to release pent-up frustrations and emotions. Set aside a few moments each day to write down your thoughts in a notebook or on a phone or tablet.

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PANS and PANDAS: Acute-Onset OCD in Children - HelpGuide.org

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Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a childhood condition characterized by the sudden onset of obsessive-compulsive symptoms (OCD) and/or eating restrictions following a bacterial or viral infection, including COVID-19. These sudden changes often appear in combination with behavioral and neurological changes such as new fears, anxiety, depression, tics, changes in temperament, and sensory sensitivity that causes increased urination or sleep disturbances.

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Clinic opens in Mesa with focus on pediatric

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Parents Fighting PANDAS, a Disorder Most of Us Have Never Heard of, But Need to be Aware of

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Foundation for Children With Neuroimmune Disorders

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Interview With Dr. Jennifer Frankovich On PANS And PANDAS

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Beyond the Diagnosis Interview on PANDAS/PANS

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Why "My Kid is Acting Crazy" Might be PANS/PANDAS with Dr. Roseann Capanna-Hodge HPC: E102

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/ CBS Pittsburgh

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VERONA (KDKA) -- It's a rarely understood but prevalent childhood condition believed to affect one in 200 children in the United States.

Parents say it is like their child changed overnight, but now a local doctor is on a personal mission to be on the cutting edge of treatment and diagnosis.

Dr. Elizabeth Spaar put herself through medical school and now has her own practice, Family Spectrum, in Verona.

Dr. Spaar is the only doctor in the area specializing in what's called PANDAS, a childhood onset condition.

PANDAS, or Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcus, is an infection after strep throat that can suddenly and adversely affect a child's mood or behavior, cause tics and more.

"It's not normal if you're going through a phase for your handwriting to deteriorate, it's not normal if you're going through just a phase to be getting bad headaches," Dr. Spaar says.

Dr. Spaar says it's the combination of childhood psychiatric issues along with neurological issues that can lead to a PANDAS or PANS diagnosis, which can cause brain inflammation.

It's now believed infections other than strep, like sinus infections, Lyme, allergies and even exposure to toxins, can cause the childhood condition.

There's a very personal reason why Dr. Spaar began the journey to becoming a doctor specializing in the disease.

Two of her four children have the condition.

Max and his older brother had the toughest time. They were seen by 15 doctors before they were diagnosed with PANS/PANDAS.

"I get really sad that my two older boys lost 10 years to this, they lost their childhood to this," she says.

Dr. Spaar says they once had to have a designated room for Max due to his episodes of rage. But now Dr. Spaar is treating patients just like her son with an integrative treatment of Ibuprofen, antibiotics, vitamins, and sometimes, in cases like Max's, medicinal marijuana.

Eric Spaar, Dr. Spaar's husband, says the treatment combined with a tincture of medicinal marijuana under his tongue or by pill gives Max more clarity of thought.

"It calms him down and makes him have less tics," said Eric.

Max isn't the only child seeing a difference.

Dr. Spaar is getting calls from all over Pittsburgh, the United States, and even the world to help kids with PANS/PANDAS.

"Because I figured this out, I'm able to help families get their children back. You get a lot of families hugging and crying because they got their kid back," she said.

For more information on Dr. Spaar's practice, visit: https://www.spectrumfamilypractice.com/

And for additional details, visit: http://www.pandasnetwork.org/

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Pittsburgh Doctor Making Big Strides In Treating Debilitating, Misunderstood Childhood Condition

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CBS Pittsburgh Follow KDKA-TV: Facebook | Twitter VERONA (KDKA) -- It's a rarely understood but prevalent childhood condition believed to affect one in 200 children in the United States. Parents say it is like their child changed overnight, but now a local doctor is on a personal mission to be on the cutting edge of treatment and diagnosis.

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Q&A: Understanding PANS, Pediatric Acute-onset Neuropsychiatric Syndrome

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Loal Doctor On Mission To Diagnose, Treat Kids With PANS/PANDAS

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A proposed bill asks for aid in research of PANDAS autoimmune disorder

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PANS leaves parents feeling like they're living with strangers: Extended story

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PANS and PANDAS syndrome: GPs and parents call for more research into rare illness | 5 News

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Kids suffer from debilitating episodes after recovering from strep throat (Nightline)

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At 7 years old, Paul Michael Nelson was the kind of quiet, brilliant kid you were likely to find in Silicon Valley - captivated by Legos, self-taught in origami, loving and sweet. But on March 2, 2009, he woke up in the middle of the night, monstrously changed. He tore up the flooring in his bedroom. He got hold of a knife and stabbed holes through his door. He began speaking a strange language no one could understand. He tried pulling his teeth out. He barked like a dog.

His parents hustled their son to the psychiatrist, leading to an alphabet soup of diagnoses: ADHD (attention deficit hyperactivity disorder), OCD (obsessive-compulsive disorder), ODD (oppositional defiant disorder), bipolar disorder, autism and, ultimately, straight-up psychosis. Yet no matter what medications Paul Michael tried, treatment failed. He leaped from moving cars. He broke the windows in his room, causing the family to install Plexiglas. For the Nelsons, 2009 included 15 trips to the emergency room, two months in and out of psych wards and calls to the sheriff to remove a violent, raging Paul Michael from the home.

Thus commenced years of trial-and-error therapy, conducted mostly in a psychiatric ward. Frankovich and her colleague, psychiatrist Margo Thienemann, first prescribed steroids to dial down Paul Michael's immune response. But the symptoms abated only slightly, and his small body ballooned. Then, they shut down his immune system altogether with the chemotherapy drug Rituximab. To boost it back up and keep inflammation down, they added intravenous immunoglobulin, or IVIG, a total immune system-replacement made from the blood of thousands of healthy individuals. Frankovich hoped the approach would work, but Paul Michael's brain was potentially damaged, she warned, and it could take years to repair. It was late in 2013 when sweet, smart Paul Michael, rescued by years of treatment, finally stepped out of the psych ward and back into his life. Today a gentle young man of 15, he goes to public school and hopes to be a pastry chef. "He's an amazing baker," says his mother, Mary Nelson.

For years, Paul Michael Nelson struggled with a mysterious autoimmune disorder called PANS. Thanks to pioneering research, Paul Michael, now 15, is more himself these days. Here, he cuddles with his family's kitten. (Credit: Courtesy of Mary Nelson)

For Frankovich, Paul Michael was patient zero - her first encounter with a newly recognized, still-controversial diagnosis called pediatric acute-onset neuropsychiatric syndrome, or PANS.

PANS is thought to be an inflammatory condition that results when an infection or some other invasive trigger spurs the body to turn on itself and attack structures in the brain. For years, scientists had focused on a single infection - group A streptococcal disease - that produced antibodies that attacked the part of the forebrain involved in forming habits, resulting in OCD. Today, the paradigm has widened into a much bigger idea that expands our understanding of psychiatric disease: A whole host of infections and other unknown triggers lead to the production of antibodies and immune cells that can cross into the brain. Depending on where these immune responses land and which brain structures they block, erode or destroy, a range of psychiatric ills can result. In one person, it could be OCD; in the next, it could be hyperactivity and inattention, anxiety, restricted eating, even hallucinations or autistic behavior.

When these symptoms are caused by immune disorders, standard psychiatric therapies that balance neurotransmitters are unlikely to work alone. Instead, immune therapies are the first line of treatment. At Stanford and elsewhere, the hunt is on for treatment cocktails that quell the inflammation and new strategies to keep a rogue immune system at bay.

Confronting a Mystery

Scientists have long known that infection can cause neuropsychiatric disease. One of the first known examples was syphilis, a sexually transmitted disease caused by the bacterium Treponema pallidum . Until we learned to treat syphilis with antibiotics, it was one of the most common causes of dementia and was frequent among the insane. Likewise, some have proposed that Bartonella , the microbial cause of common cat scratch fever, can sometimes induce anxiety, rage and psychosis. These diseases are caused by living organisms active within the brain itself. Rid the brain of the organism early enough and the symptoms subside.

Frankovich and her team weren't the first to encounter this devastating state of affairs. For decades, a respected but beleaguered group of scientists had gathered increasing evidence that one particular bacterial infection - strep - led to the body pumping out antibodies that attacked the brain, causing OCD and tics. Because they limited the syndrome to strep infection alone, they came up with the tongue-twisting label of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, or PANDAS.

The idea that OCD was a chemical imbalance in the brain goes back to the 1980s and psychiatrist Judith Rapoport, chief of child psychiatry at the National Institute of Mental Health (NIMH). Trying to find the right medicine for the sickest of these patients, Rapoport scanned their brains to zero in on regions involved in OCD and found increased activity in the basal ganglia, a center for movement and habits located at the base of the forebrain.

Not long after, Rapoport's protégé, pediatrician Susan Swedo, who now leads the NIMH's section on behavioral pediatrics, took notice. She proposed that one rare neurological disorder, Sydenham chorea, could shed some light on the OCD and tics the team had observed.

Swedo's reasoning made sense. Sydenham is an autoimmune illness characterized by rapid, involuntary, purposeless movements, especially of the face, feet and hands. And it results as a complication of catching strep, which evades the human immune system by adapting its outer surface to resemble human biomolecules, a phenomenon called molecular mimicry. The bacteria can seem so similar to human tissue that antibodies produced against it attack human organs as well.

Left untreated for as little as five days, strep could produce autoantibodies that damage heart tissue, resulting in rheumatic fever. Sydenham chorea was like rheumatic fever of the brain, thought to occur when rheumatic fever progresses and strep antibodies (emboldened by fever) breaches the blood-brain barrier (BBB), the tight wall of endothelial cells ordinarily there to protect the brain from the outside world. Once they break into the brain, the autoantibodies attack the basal ganglia, causing the afflicted to jerk and writhe in a manner resembling the worst cases of the tic syndrome Tourette's. Because OCD also is often accompanied by tics, though perhaps not as severe, Swedo's medical model of Sydenham could work.

To see if the concept held - and whether Sydenham chorea even caused OCD - Swedo and her partner at NIMH, psychiatrist Henrietta Leonard, conducted a retrospective study in 1989 of three sites in the United States that had rheumatic fever outbreaks: Salt Lake City, the Ohio River Valley and Walden, Penn. Comparing children with and without Sydenham chorea, the duo found support for Swedo's proposal: Two-thirds of children with Sydenham chorea actually had obsessive-compulsive behaviors and thoughts. A critical revelation of the study was that the OCD appeared "about two weeks to a month before the movements did, often suddenly and out of the blue," Swedo says.

After the survey, her team at NIMH began seeing Sydenham children who were at the height of the disease. "We brought them in from all over the United States, and you couldn't make these stories up," Swedo says. "One of the boys had a very classic fear that school was contaminated and made his brother leave his shoes outside the house. Then they stepped inside the house and they had to take their socks off. And his mother had to wash those socks right away."

As a pediatrician, Swedo felt compelled to help these children with Sydenham, but neuropsychiatric medications focused on rebalancing brain chemistry just didn't work. So she began to consider treating the autoantibodies themselves. By the early 1990s, Swedo and the NIMH team were treating the Sydenham group and pioneering some of the same types of treatments used for patients like Paul Michael today: steroids such as prednisone to stanch the tide of immune molecules; plasmapheresis, a technique to filter the blood, cleanse it of autoantibodies, and return it intact to the patient; and intravenous delivery of a new, healthy immune system with IVIG.

But as Swedo and colleagues studied data from the drug trials for their Sydenham patients and controls without the disease, they found something else. Not just in the extreme situation of Sydenham's, but even with ordinary strep, autoantibodies appeared to careen though the brain, causing less severe forms of tics and OCD.

Discovering a New Disease

Ultimately, three brothers in Swedo's clinic helped her grasp what was going on: The oldest had a diagnosis of Tourette's syndrome with physical tics. The second child had some tics. And the youngest had tics and movements so extreme that doctors diagnosed him with Sydenham chorea.

"He also presented to the clinic with very severe hoarding," Swedo recalls of the youngest. "He carried a brown paper bag with him and if he saw a piece of paper, he'd put it in the bag. After he came the first time, we had enough sense to clear the magazines out of the waiting room." The child also had an "incredibly complex tic where he waved his arm around just huge and he also was kind of floppy."

But the youngest brother, it turned out, did not have Sydenham. Instead, he had developed his psychiatric symptoms as the result of a more ordinary strep infection. "He was the first PANDAS case," Swedo says. The boys' mother, a medical technologist, helped to connect the dots. Her eldest son, the one diagnosed with Tourette's, had tics that waxed and waned. Whenever his symptoms reached a peak, his throat cultures tested positive for strep. Now Swedo and her team saw the picture clearly: Ordinary strep infection could cause neuropsychiatric symptoms in a far broader, more under-the-radar group of patients.

The strep model worked perfectly for Tanya Murphy, a University of South Florida psychiatrist who'd been observing the infection's footprint for years. Murphy had found that right after strep, psychiatric ills could suddenly manifest: not just OCD, but eating disorders like anorexia. "And these weren't typical anorexia patients worried about body image," she says. Like the OCD patients themselves, "mostly, they were worried about contamination."

Murphy's work, which spans two decades, helped to define the population in a nuanced way. As early as 2006, she established that children with OCD from PANDAS had truly toxic behavioral reactions to the same dose of serotonin-based medications that brought relief to those with standard forms of OCD. It was clear the two groups were not the same.

That connection was strengthened by immunologist Madeleine Cunningham, a rheumatic fever expert from the University of Oklahoma. Swedo recruited her in 1999 to explore what autoantibodies from strep could do to the brain. It was a wild ride. Cunningham and her postdoc at the time, Christine Kirvan, found that the antibodies literally bind to human neurons, activating an enzyme called calcium/calmodulin-dependent protein (CaM) kinase II. When patients had high levels of activated CaM kinase II floating around in their brains, nerve cells got overstimulated, and symptoms of OCD or a movement disorder could erupt. The protein marker offered a blood test for PANDAS.

But that represented just part of the damage. Cunningham found that the same patients produced autoantibodies targeting lysogangliosides, molecules within the membranes of nerve cells in the brain. Although it hasn't been demonstrated yet, autoantibodies attacking these lysogangliosides are thought to disrupt nerve cell signal transmission and, presumably, the behavior of the patients. The autoantibodies also attached to tubulin, a protein molecule used to maintain a cell's physical structure. Cunningham suspects that when the strep antibodies target tubulin in the brain, the result is a gumming up of a cell's structural machinery and, apparently, neuropsychiatric ills. More recently, Cunningham has found that strep antibodies target brain receptors for dopamine, a neurotransmitter important for cognitive focus.

Settling a Dispute

For years, such findings were met with the salvos of critics insisting the very notion of PANDAS was a fantasy - an absurd concept at loggerheads with neurology and logic.

How ridiculous, those critics said: Since 60 to 70 percent of children catch a strep infection at some point, naturally those with OCD or tics would, like everyone else, show evidence of exposure in their blood. Swedo, Murphy and others claimed that tics in kids with PANDAS appeared suddenly, yet, critics argued, the same was true for tics in Tourette's, so how could you tell them apart?

The dispute came to a head in 2010 at a contentious meeting at the National Institutes of Health. Swedo, Cunningham, Murphy and crew dropped their claim that the phenomenon caused tics ("even though we usually see them," Swedo says). But they and critics in the field were able to agree that infection wasn't a necessary trigger for symptoms, widening the scope of the phenomenon way beyond strep.

A New Diagnosis of Hope

Now, researchers have further refined their understanding of the syndrome, and a series of powerful new studies published over the past couple of years have helped establish autoimmunity's role in neuropsychiatric disease.

In the time since that tense 2010 NIH meeting, Murphy set out to study 43 children recruited soon after the sudden onset of OCD, capturing the early characteristics of the disease. The children were so impaired that a third of them had to be home-schooled. A large number had trouble eating due to fear of food; one was so dehydrated she was sent to the ER. Infectious triggers included strep and the bacterium mycoplasma.

Given these findings, Murphy treated the kids with azithromycin, an antibiotic that targets both infections. And she saw improvement, especially in kids with the most severe tics.

Tracing each illness back to the start of symptoms, Frankovich has managed to find clusters: groups of children from the same school or neighborhood who had all come down with the condition in the same month; individuals with a true, physical connection, like the family of three brothers Swedo had studied years before. In the course of her investigation, a host of alternate infections have emerged: not just strep, but bacterial mycoplasma, influenza, sinusitis, pneumonia and others.

By 2015, Frankovich and her team had led the effort to create treatment guidelines for PANS patients. Though many young people in the Stanford PANS clinic had OCD, their psychiatric illnesses went well beyond that: 40 percent had suicidal thoughts; 19 percent had homicidal thoughts; and nearly two-thirds were at risk of committing violent acts. Some 26 percent had psychosis. This wide assortment of symptoms has Frankovich on a quest to identify subgroups in the hopes of tailoring treatments, but she longs for the day she can find and use a full array of biomarkers signaling disease and genetic risk. "Maybe we really have 10 disorders," she says. "Maybe strep-triggered PANS is different from flu-triggered PANS. This is a real disease, but we need more research to learn where the true lines lie and many treatment trials to understand the best therapies."

Peering Into the Brain

One promising tool is the "Cunningham Panel," created by Cunningham through her commercial lab, Moleculera. Currently used for patients with neuropsychiatric symptoms, blood tests in the panel search for the autoantibodies Cunningham has found. The tests also look for whether the blood increases CaM kinase II activity.

The real hope, of course, is for more effective treatments targeting the underlying problem to replace these harsh therapies. Toward that end, potentially game-changing research comes from Dritan Agalliu, a vascular biologist and blood-brain barrier expert at Columbia University Medical Center in New York. Funded to focus on PANS by two wealthy parents whose child was diagnosed with the disease, Agalliu began searching in 2012 for controls to the trap door that autoantibodies use to sneak into the brain.

He exposed specially bred mice to strep and scrutinized their brains after death. How did repeated strep infection alter the integrity of the BBB? How did it induce rapid onset of neuropsychiatric disease?

One finding was that strep eventually led to massive production of a certain kind of immune cell, Th17, along with inflammation of the brain. In humans and rodents alike, Th17 cells take on the role of a conductor, telling other immune cells what to do. They have been implicated in the destruction of the BBB and are found in increased numbers in many autoimmune diseases. In the experimental mice, Agalliu saw that Th17 cells had poked holes in the BBB, opening the floodgates into the brain. Inside the brain, strep bacteria were nowhere to be found, but there were plenty of antibodies normally kept out by a healthy BBB.

Agalliu also found that Th17 cells induced by strep opened the BBB only in certain spots: Since strep enters the body through the nose, it made sense that he saw the BBB was pierced near the olfactory bulb, the structure in the front of the brain that processes odors. But strep also caused a leak in the BBB near the amygdala, the seat of fear and anxiety, and the lateral hypothalamus, where our sense of hunger begins. Given the primary PANS symptoms of OCD, anxiety and anorexia, this fit quite well. It's possible that finding ways to repair the BBB or safely block Th17 cells would better treat PANS patients.

Another potential tactic involves pumping the immune cells and toxic molecules out of the brain - considered a futile quest until just a couple of years ago. That's when University of Virginia neuroscientist Jonathan Kipnis and his team discovered a hidden core of vessels - a previously unknown sewage system for draining cellular waste from the brain into the lymph system at large. The work is in mice, but preliminary evidence suggests humans have it, too.

"Its existence," Kipnis says, "could explain how Alzheimer's plaque can be cleaned out by some of us but left for sludge in those who get disease. In some people, the vessels no longer work efficiently." The point for PANS: In diseases of autoimmunity, where rogue immune cells are stuck in the brain, returning these lymphatic vessels to greater function may be a potent means of clearing up disease.

These newest discoveries are so early that they won't enter the therapeutic arsenal without a wealth of additional research. And even where therapies have a track record, physicians (and parents) must differentiate between psychiatric disease, infectious disease and autoimmunity with care. Perhaps the best guideline here is that when psychiatrists call patients untreatable and show them the door, it only makes sense to explore PANS as another possible cause.

That unlikely detour brought reprieve to Paul Michael Nelson and his parents, who spent four years navigating violent rages and psychotic symptoms so overwhelming that the boy seemed forever lost. The Nelsons feared their child was, in many ways, dead. Tamping down his overactive immune system brought him back.

A Syndrome Evolves

PANS is just the latest acronym for the constantly evolving neuropsychiatric disorder. Here's the name game researchers have played to get there and how those names fit into our current understanding of the syndrome:

In 1995, in the Journal of the American Academy of Child and Adolescent Psychiatry, Susan Swedo and Henrietta Leonard reported on five cases of a syndrome they called PITANDs - pediatric infection-triggered autoimmune neuropsychiatric disorders. Their sweeping hypothesis held that OCD and tics could be triggered or exacerbated by a host of infections, including strep, influenza and chickenpox.

In 1998, Swedo pulled back from this broad-brush theory, focusing just on strep to raise awareness and create a medical model to speed discoveries. She renamed the syndrome PANDAS, for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection.

In 2010, Swedo and her colleagues met at NIH, and in a wide-ranging, collaborative group decision, they eliminated the requirement for any specific infection as a bar for the syndrome. The name of the syndrome, published officially in a 2012 paper, is now PANS, for pediatric acute-onset neuropsychiatric syndrome.

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Understanding PANS, a Frightening Condition That Can Turn Children Inexplicably Violent

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At 7 years old, Paul Michael Nelson was the kind of quiet, brilliant kid you were likely to find in Silicon Valley - captivated by Legos, self-taught in origami, loving and sweet. But on March 2, 2009, he woke up in the middle of the night, monstrously changed.

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Adam Elliott was 2 years old when his parents began to suspect he might have autism. Adam had trouble making eye contact - one telltale sign of the condition - and there were other hints as well. He was a calm, inquisitive child most of the time, but some days at preschool, he would become unfocused and uncoordinated, fumbling with scissors as he tried to cut paper for art projects.

By the time Adam entered elementary school, his traits had worsened. He began to experience severe separation anxiety and sensory overload in the noisy classroom. He became aggressive. When he was 6, for example, he believed his best friend was saying nasty things about him and scratched the friend in the face with a pencil. At home, Adam would often walk in circles, filled with anxiety. He eventually became so afraid that his food was poisoned, he refused to eat for long periods of time.

Adam's parents took him to a dozen different specialists during this time, including occupational therapists and psychologists. None were willing to attach a label to Adam's condition, recalls his mother, Wendy Elliott. One doctor diagnosed Adam with attention deficit hyperactivity disorder (ADHD) and prescribed amphetamine/dextroamphetamine (Adderall), but it did little to quell the boy's obsessive thoughts and behaviors.

By 2015, when Adam was 8, Elliott began to fear she might have to have him hospitalized. She took him for a full psychological evaluation with Rebecca Daily, an autism specialist at the University of Oklahoma. During the visit, Elliott mentioned that Adam's problems had all started when he was a toddler, around the time he had had his tonsils and adenoids removed. Doctors had recommended the surgery because he had had so many bouts of strep throat.

"What did you say?" Daily asked.

Elliott repeated what she had said.

She remembers Daily then saying: "This is not autism, this is not ADHD. This is a disease called PANDAS."

Elliott had never heard of PANDAS, short for 'pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.' But the diagnosis had been gaining traction over the previous two decades. In 1998, Susan Swedo, then a pediatrician at the U.S. National Institutes of Health (NIH), first proposed PANDAS to explain an apparent association between strep throat, obsessive-compulsive disorder (OCD) and tic disorders such as Tourette syndrome. By Swedo's estimate, the condition affects up to 1 in 200 children, but many experts contest that figure - and even the condition's very existence.

Pediatric neurologists point out that Tourette syndrome and OCD are highly heritable; if strep plays a role in these conditions at all, it is extraordinarily rare. Strep, by contrast, is common. In one study that followed 814 children for 12 weeks, for example, about half of the children had ongoing strep infections, and they did not show more obsessive-compulsive behaviors or tics than the other children.

Still, PANDAS has attracted a vocal band of proponents who have proposed it as a catchall for a wide range of mental health issues sometimes lumped under the broader term ' autoimmune encephalopathy.' The list of purported triggers has grown from strep to include Lyme disease, mononucleosis and herpes. And the range of possible outcomes has expanded to encompass ADHD, anorexia nervosa and autism. The boundaries between these diagnoses can be subjective, and some clinicians and parents are quick to attribute obsessive-compulsive behavior to PANDAS, even when it may stem from autism, OCD or something else. "There's going to be diagnostic confusion whether a child has a late presentation of autism or if they have PANDAS," Swedo says.

Daily recommended that Adam take a test developed by a colleague of hers, microbiologist Madeleine Cunningham. Oklahoma-based Moleculera Labs, which Cunningham co-founded, markets the $925 test - called the 'Cunningham Panel' - for children who are not responding to treatments for psychiatric conditions and who may instead have "a treatable autoimmune disorder." One brochure reads: "Could an infection be causing your child's symptoms?"

Whether they pursue the test or not, parents who suspect their child has PANDAS often end up seeking expensive, unproven and potentially dangerous treatments - including, in rare cases, rituximab, an immunosuppressant typically used for cancer treatment and organ transplants that has serious, sometimes deadly, side effects. Medical quacks and profiteers have thrived, largely unchecked in a marketplace that intersects with the outer fringes of the autism and chronic Lyme communities. One Oklahoma company, for instance, markets donkey milk as a PANDAS treatment. Most parents end up paying out of pocket, but five states have passed laws mandating insurance coverage for treatment of the condition.

The condition's rising popularity notwithstanding, several experts say the way it is being diagnosed and treated is worrisome. "Allow me to be considered a naysayer," says Edward Kaplan, an expert in streptococcal infections at the University of Minnesota in Minneapolis. He says there may be a neurological trigger for the behavioral changes in some children diagnosed with PANDAS, but the link to strep is tenuous at best. "This disease is diagnosed by all kinds of people more frequently than perhaps it should be."

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How a controversial condition called PANDAS is gaining ground on autism | Spectrum | Autism Research News

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Adam Elliott was 2 years old when his parents began to suspect he might have autism. Adam had trouble making eye contact - one telltale sign of the condition - and there were other hints as well.

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What Are PANDAS and PANS?

PANDAS and PANS cause a sudden onset of severe OCD symptoms. They also cause other sudden changes in a child's behavior. These can be so extreme that a parent may say their child seemed to "change overnight."

PANS and PANDAS can be treated with medicines and therapy. Doctors and mental health experts can also give families guidance and support to help get through the challenging times.

What Are the Symptoms of PANDAS and PANS?

Kids with PANDAS and PANS will have sudden and severe obsessions, compulsions, or both.

Obsessions. A child may have new and intense fears. Or new and intense concerns about things being even, clean, dirty, or a set way. Stressful thoughts or images may come to mind over and over. These fears, thoughts, and concerns can be so strong that a child may be hard to comfort.

Compulsions (rituals). A child may wash, touch, do, or repeat things, and feel unable to stop. For example, they may walk in and out of a doorway many times, trying to do it "right." They may ask a parent for reassurance over and over.

Kids with PANDAS and PANS will also have other new symptoms. These can include:

tics or jerky movements

anxiety, depression, or mood swings

acting aggressive or "hyper"

using baby talk, acting clingy, or having new bedtime fears

sudden trouble with handwriting or other fine motor skills

new trouble with memory, reading, or math

new bedwetting, not sleeping

new fears about foods, eating, or choking; not eating

new sensitivity to noise, touch, clothes, or light

What Causes PANDAS and PANS?

Experts believe PANDAS and PANS happen because of a problem with the immune system's response to an infection.

Instead of attacking the germs, the immune system targets a part of the brain by mistake. This part of the brain is called the basal ganglia. It affects thoughts, feelings, movement, and other behaviors. Experts believe irritation in this part of the brain leads to the symptoms.

What's the Difference Between PANDAS and PANS?

The most common cause of a severe onset of OCD and tics is a Group A Streptococcus ("strep") infection. When it's clear that a child's symptoms are linked to a strep infection (like strep throat), it's called PANDAS. It stands for Pediatric Acute-onset Neuropsychiatric Disorders Associated with Streptococcus.

PANS is when the severe onset of OCD symptoms is linked to another infection. These include the flu, chickenpox, mycoplasma, and Lyme disease. PANS stands for Pediatric Acute-onset Neuropsychiatric S yndrome.

How Do Doctors Diagnose and Treat PANDAS and PANS?

Most children with OCD did not get it because of PANDAS or PANS.

To diagnose PANDAS or PANS, doctors will take time talking to you and asking questions about your child's symptoms. They will do an exam and test for infections.

Treatment starts with medicine to take care of the infection.

Treatment also includes cognitive behavioral therapy for OCD. This is done by a trained mental health provider. Your child's doctor can refer you to the right person.

Therapy for OCD includes exposure and response prevention. This part of therapy reduces the ritual behaviors.

Therapy can also address other behavior and mood symptoms that may be part of PANDAS or PANS. For example, a therapy called habit reversal can help if a child has tics.

Therapists work closely with parents to coach them in ways to help their child's symptoms improve. Therapists also guide parents on how to manage a child's stressful symptoms until they can resolve.

Are PANDAS and PANS Contagious?

No. PANDAS and PANS are not contagious. Kids can't catch them from someone else. Both PANDAS and PANS are rare.

How Can I Help My Child?

If you think your child may have PANDAS or PANS, contact your child's doctor right away.

It's best to start therapy as soon as you can. Your doctor can help you find a mental health therapist. Or visit the International OCD Foundation website to find an expert who is trained to provide cognitive behavioral therapy for OCD in children.

To help your child get better:

Start working with a therapist right away.

Make sure your child does not miss any therapy sessions.

Ask the therapist about the best ways to comfort or soothe your child.

Give your child all the medicines your doctors recommend.

Give your child a new toothbrush to be sure all the germs are gone.

Watching a child go through symptoms of PANDAS or PANS is stressful and challenging. Your care team is there to support and guide you. Lean on them for help and advice.

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PANDAS and PANS cause a sudden onset of severe OCD symptoms. They also cause other sudden changes in a child's behavior. These can be so extreme that a parent may say their child seemed to "change overnight." PANS and PANDAS can be treated with medicines and therapy.

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0:00 / 7:12•Watch full video

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How Immune Response to Strep Infection Triggers BGE Breakdown of Blood Brain Barrier PANDAS/PANS

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If your pediatric patient is presenting with an acute and dramatic onset of psychological distress,
CONSIDER PANS/PANDAS.

PANS/PANDAS CLINICIAN RESOURCES

FLOWCHARTS

Follow the process for determining the appropriate diagnosis and symptom severity based treatment protocols for mild, moderate, and severe/extreme cases.

DIAGNOSING PANS/PANDAS

Access published criteria, symptoms associated with PANS and PANDAS, and additional tools to help health care providers navigate evaluating their patients.

SEEING YOUR FIRST PATIENT

This publication helps clinicians new to PANS/PANDAS by providing an overview, symptoms and diagnostic criteria, workup recommendations, and expectations.

RECRUITING: PANS/PANDAS IVIG STUDY

Researchers are seeking participants between the ages of 6-17 with a confirmed diagnosis of moderate to severe PANS/PANDAS to enroll in a trial to determine the sustainability of the reduction of the severity of symptoms in children treated with intravenous human normal immunoglobulin and to assess its efficacy in reducing functional impairment associated with PANS/PANDAS.

PANS CHILDREN MAY MANIFEST POTS-2022

Frontiers in Neurology paper describes a higher prevalence of POTS (Postural Orthostatic Tachycardia Syndrome) in patients with PANS than in the general pediatric population and an association of POTS with comorbidities such as joint hypermobility, anxiety, chronic fatigue, and family history of cardiovascular issues. We also observed that POTS was more likely observed during a PANS flare. It is interesting that immune dysfunction, which is present in PANS, may be implicated in some individuals with PANS and POTS.

A Conversation with Stanford’s Jennifer Frankovich, MD, MS

Post Infectious Inflammatory Brain Disorders and PANS/PANDAS
Dr. Frankovich is a Clinical Professor in the Department of Pediatrics, Division of Allergy, Immunology Rheumatology at Stanford University/Lucile Packard Children’s Hospital and Co-director of Stanford’s Immune Behavioral Health Clinic.

PANS/PANDAS RESEARCH AND LITERATURE

OUR MISSION

The PPN mission is to maintain the industry standard PPN Guidelines for Diagnostics and Therapeutics, foster continuous education and communication within the multi-disciplinary medical community and to sponsor research for developing diagnostic tests, treatment protocols and a cure for PANDAS/PANS within this generation.

BECOME A MEMBER

► Receive email alerts on new research, guidelines, and treatment protocols
► Option to be recognized as a practitioner who works with PANS/PANDAS patients
► Become eligible to apply for a research grant
► Receive occasional members only benefits

ADVISORY COMMITTEES

Public Health Advisory Committees for PANDAS and PANS are done through a collaboration of health care and community-based partnerships. The list of committees are organized by state.

CHANGE THE COURSE OF MENTAL ILLNESS

PPN is dedicated to impacting the research and education of PANS/PANDAS. Your donation to PPN will give physicians and medical professionals the resources they need to diagnose PANS/PANDAS in the early stages of the illness and promptly begin treatment. We are determined to help those suffering now while simultaneously working to fund research that will lead to a cure. Your support makes this possible. Thank you!

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PANS/PANDAS resources to help clinicians diagnose and treat their patients.

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Strep throat is a common childhood illness. Some kids get it again and again, and a simple round of antibiotics usually clears it up. But for a small number of children, the infection triggers strange behavior changes known as PANDAS syndrome: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections.

With PANDAS, your child may seem to turn into a different person overnight, becoming moody, anxious, aggressive, obsessive compulsive behaviors, and dealing with body movements they can't control. It can be scary, but once your child is diagnosed with PANDAS and starts treatment, it's likely they'll make a full recovery.

How is it diagnosed?

A test for the strep bacteria or a history of the bacteria is necessary to confirm your child has PANDAS, which can mimic other disorders. If it doesn't show up after a throat swab or antibody test, the doctor should check other places strep tends to hide, like the sinuses or your child's bottom and genitals. A blood test can show whether your child had a recent strep infection even if they recovered.

If your child doesn't or didn't have strep, they don't have PANDAS. But their symptoms could still be part of an immune system response gone wrong. PANDAS is part of a larger group of autoimmune diseases that affect the brain called pediatric acute-onset neuropsychiatric syndrome (PANS). The symptoms are similar, but they may be triggered by something other than strep. Your child's doctor may order blood tests or brain scans to see if a different infection or something else entirely is causing the symptoms.

Not all doctors have experience diagnosing PANDAS. Your child may need to see a rheumatologist or an immunologist, or someone who specializes in strep infections. A referral to a psychiatrist or psychologist will probably be part of the treatment plan.

Antidepressants. Medications called selective serotonin reuptake inhibitors (SSRIs) can help manage OCD. But they can be dangerous for children, and kids with PANDAS seem to be especially likely to have side effects. If your doctor recommends them, make sure you understand the right dose to give and any problems to watch for.

. If other treatments don't work, or your child's symptoms are so severe they can't function, their doctor might consider a more extreme procedure to reset their immune system. One option is IVIG, an infusion of antibodies from other people, delivered through a vein. In another option, plasmapheresis, doctors remove blood from your child's body and filter it through a machine that removes the antibodies that are attacking their brain.

Will my child get better?

Although it may take time, most children who have PANDAS recover completely with treatment.

Symptoms tend to slowly get better over several months once the strep infection clears, but there may be ups and downs.

PANDAS is likely to come back if your child gets strep again. Sometimes all it takes is exposure to the germ. To help your child stay healthy, teach good hygiene habits: wash hands, change toothbrushes often, and stay away from sick people. Your whole family may need to get tested for strep to make sure no one is carrying the bacteria.

Your pediatrician may prescribe antibiotics long-term to try to prevent new strep infections. Some children have their tonsils removed. But scientists haven't studied either of these strategies enough to know whether they work.

It's rare for kids older than 12 to have reactions to strep infections. But that doesn't mean your teenager is out of the woods. Very little research has looked into whether PANDAS can show up in older kids or adults. So it's important to know the symptoms and get medical help quickly when they seem to appear.

What treatments are there?

The sooner you can diagnose and treat PANDAS, the better the chances are that the symptoms will go away. Treatment usually involves medication and therapy.

Antibiotics. Your child's doctor will treat the underlying strep infection with antibiotics. It usually takes a week or two, although some kids improve within days. You may have to try more than one antibiotic to find what works.

Anti-inflammatories. These drugs can calm the immune system. Your child may get a steroid pill for several days. Nonsteroidal anti-inflammatory drugs ( NSAIDs) like ibuprofen may also help.

Cognitive behavioral therapy. While medications fight the infection, therapy can help control the OCD. A therapist will give your child strategies to deal with OCD thoughts and fears. It's important for you to learn what goes on in therapy so you can help your child apply it at home.

What causes it?

Doctors aren't sure why some children get PANDAS, but it appears to be an autoimmune disorder. That's when an infection causes your immune system to attack your body's healthy cells, in this case, cells in the brain. The strep bacteria disguise themselves to look like normal cells. When the immune system eventually finds and fights them, it sometimes also fights the cells that the strep is imitating.

What are the symptoms?

Children with PANDAS suddenly show signs of obsessive-compulsive disorder ( OCD,) tics, or both. The changes to their personality and behavior are quick and dramatic; they start abruptly and closely after a strep throat infection.

OCD causes thoughts they can't put out of their mind, or an urge to repeat certain actions over and over.

Tics are sudden movements or sounds your child repeats over and over and can't control. They may blink a lot or jerk their head. They may grunt, clear their throat constantly, or repeat words.

If your child already has OCD or tics, PANDAS will suddenly make their condition much worse.

Other symptoms include:

Uncontrolled, jerky movements

Symptoms of ADHD, such as hyperactivity, fidgeting, and trouble paying attention

Anxiety attacks or fear of being away from parents or other caregivers

Depression

Behavior they'd grown out of, like temper tantrums or baby talk

Moodiness, irritability, and crying or laughing at inappropriate times

Sensory problems, including being very sensitive to light and possibly seeing or hearing things that aren't there

Sleep problems

Bed-wetting, peeing more often during the daytime, or both

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Strep throat is a common childhood illness. Some kids get it again and again, and a simple round of antibiotics usually clears it up. But for a small number of children, the infection triggers strange behavior changes known as PANDAS syndrome: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections.

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Anyone have kids with this dx? I have student who was dxd in 3rd grade (now 9th) w/Lyme. Has had terrible attendance since then (Lyme is not currently active to the best of my knowledge) but has had awful strep and tonsillitis this year several times and is scheduled for T&A soon.