Strep throat is a common childhood illness, but in a few children this bacteria infection can lead to alarming, lasting changes in behaviour.
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AI Summary
A seemingly harmless strep throat infection can, in rare cases, trigger a severe and sudden psychiatric disorder in children known as PANDAS (Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections), or a broader condition called PANS.
Key Points:
Case Study:
Charlie Drury was a healthy 8-year-old until he suddenly developed strange symptoms—tics, OCD, hallucinations, aggression, and sensory issues—shortly after being diagnosed with strep throat in 2012. He was eventually diagnosed with PANDAS.
What Is PANDAS/PANS?
These are autoimmune disorders where a child’s immune system, after fighting an infection (typically strep), mistakenly attacks their brain, especially a region called the basal ganglia, affecting motor control, emotions, and behavior.
Symptoms:
Sudden-onset OCD, tics
Mood swings, aggression
Sensory sensitivity
Developmental regression
Hallucinations, insomnia, eating issues
Diagnosis Challenges:
No definitive test or biomarker
Brain scans often look normal
Often misdiagnosed as psychiatric illness
Some doctors remain skeptical
Triggers Beyond Strep:
Other infections like flu, COVID-19, or Lyme disease can cause similar symptoms (more broadly called PANS).
Treatment Difficulties:
Early treatment (antibiotics, steroids, etc.) is most effective
Severe or long-term cases may need IVIG (immunoglobulin therapy) or plasma exchange
Many families struggle to access proper care due to medical skepticism and insurance issues
Tragic Outcome:
Lulu Johnson, an 11-year-old girl, suffered a rapid onset of symptoms in 2019 and died in 2021 after a long battle with PANDAS. Her family donated her brain for research to help uncover better understanding and treatment options.
Ongoing Efforts:
Growing recognition by health authorities like the WHO
More research needed to understand mechanisms, develop biomarkers, and establish standard treatments
Families and advocates push for awareness, insurance coverage, and early intervention
Conclusion:
While rare, PANDAS/PANS can devastate a child’s life and family. Misunderstanding and lack of awareness often delay diagnosis and treatment. Researchers and advocates hope to prevent future cases through better science, care, and public knowledge.
PANS has to be related to ME/CFS and long COVID, right? Sudden onset of a brain-related condition shortly after any of a number of different infections?
The AI summary says it can occur after COVID infection. If so, I'm surprised I haven't really seen it mentioned in any long COVID papers as one possible presentation.
Much more rare than ME/CFS apparently (and opposite sex bias):
One estimate says one in every 11,800 children might develop Pandas or a related condition called paediatric acute-onset neuropsychiatric syndrome (Pans) in a year, although the numbers do vary dramatically from study to study. They do, however, seem to be more prevalent among boys than girls, according to data from an international patient registry, and strikes children before puberty.
I saw a few papers that were case reports of sudden onset OCD following COVID. Maybe COVID-related PANS is too rare for anything other assorted case reports.
SARS-CoV-2 related paediatric acute-onset neuropsychiatric syndrome, 2021, The Lancet: Child & Adolescent Health | Link
SARS-CoV-2/COVID-19 associated pediatric acute-onset neuropsychiatric syndrome a case report of female twin adolescents, 2022, Psychiatry Research Case Reports | Link
New-Onset OCD and Juvenile Enthesitis-Related Arthritis after COVID-19 (Three Cases), 2025, Developmental Neuroscience | Link
If it is related to ME/CFS and it is this much rarer, I imagine it would be very hard to ever get a DecodeME size GWAS for this condition. Maybe one day, insights from ME/CFS and long COVID research will help them.
PANS has to be related to ME/CFS and long COVID, right? Sudden onset of a brain-related condition shortly after any of a number of different infections?
The AI summary says it can occur after COVID infection. If so, I'm surprised I haven't really seen it mentioned in any long COVID papers as one possible presentation.
It sure sounds similar, especially the danger of infections even years after remission, however, the diagnostic criteria are different (see the attached graphic from https://www.pandasppn.org/pans/).
Other common respiratory illnesses, including influenza, have been linked to Pandas-like symptoms, too. Preliminary research also suggests Sars-CoV-2, the virus that causes Covid-19, can either worsen existing symptoms or cause new ones – perhaps by increasing inflammation throughout the body and/or reactivating other dormant viruses in the body, one 2023 study theorised. Delaney's research and clinical experience suggests that tick-borne infections that cause Lyme disease may be a catalyst for symptoms, too.
When a pathogen other than strep seems to trigger sudden-onset neuropsychiatric symptoms – or when doctors can't identify a specific trigger – children are given the more general diagnosis of Pans. Although there are other differences in their diagnostic criteria, Pandas is considered a subtype of Pans.
Infections can prove disastrous for Pans/Pandas patients for years on end, says Sarah O'Dor, a clinical psychologist at Suffolk University in Boston, Massachusetts, who until recently was the director of research for the Pediatric Neuropsychiatry and Immunology Program at Massachusetts General Hospital. Pans/Pandas symptoms wax and wane, with children experiencing periods of near or total remission that can last years. But then, "if the child gets sick again with something – it might be strep, it might be Covid – suddenly these symptoms come back," O'Dor says.
PANS has to be related to ME/CFS and long COVID, right? Sudden onset of a brain-related condition shortly after any of a number of different infections?
As I understand it, PANDAS is totally unrelated to ME/CFS, being a primarily psychiatric problem. I have never seen a case presented so presumably it is fairly rare. The basal ganglia are said to be targeted and of course Sydenham described chorea after streptococcal infection over a century ago.
Streptococci produce a range of very idiosyncratic immunological reactions that are not autoimmune as far as we know. Rheumatic fever looks like an immune complex problem and the basal ganglia issues may be too. There is really no similarity to ME/CFS.
PANS appears to be a vaguer category that may not be well validated. I do notunderstand why it is lumped in with PANDAS. But again it seems to focus on psychiatric features that are not features of ME/CFS. I think there is a lot of debate as to whether this is a useful category. I worry that it is the sort of muddled classification that we get with EDS, 'gut-brain-axis' and all that stuff. I think it may well be best to ignore. The AI Summary vertainly suggests a lot of muddled thinking.
"Psychiatric" feels to me like an almost useless term. The difference between obsessing about a specific thought (OCD), having little motivation (some forms of depression), yoyoing between high and low mood (bipolar disorder), and seeing things that are not there (schizophrenia) seem about as different from each other as any of them are from constantly having chronic pain or fatigue. ME/CFS adds some more weirdness with exertion, but unless we get some clear evidence that the symptoms are primarily caused somewhere outside the brain, I don't see any clear "psychiatric" boundary I can wrap my head around.
I can absolutely imagine that maybe in one case, someone gets an infection that interferes with a part of the brain that causes schizophrenia. An infection interferes with another part of the brain, OCD. Another part of the brain, ME/CFS.
PANS appears to be a vaguer category that may not be well validated. I do notunderstand why it is lumped in with PANDAS. But again it seems to focus on psychiatric features that are not features of ME/CFS. I think there is a lot of debate as to whether this is a useful category.
As I understand it, PANS and PANDAS are more or less describing symptoms that happen after an infection. How is this not exactly the same thing as ME/CFS or long COVID?
For all intents and purposes, OCD beginning shortly after a COVID infection can probably be classified as long COVID based on some criteria, just as ME/CFS-associated symptoms can be.
And in the sense that ME/CFS is describing one specific symptom presentation which is not specific to an infection, how is it not a similarly useful category?
Sure, there's a possibility it's so rare because a few "fringe" doctors are getting over enthusiastic with diagnoses. Or maybe it's rare just because it's rare, and OCD beginning shortly after any of a number of infections is worth studying just as much as post-exertional malaise after any infection is worth studying.
The diagnostic flowchart above looks like it makes things complicated. Maybe it's just a case of trying to get as homogenous a definition as possible so that there's some chance of seeing similar pathology between cases in these small populations.
Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome PANS by exome and whole genome sequencing
Trifiletti, Rosario; Lachman, Herbert M; Manusama, Olivia; Zheng, Deyou; Spalice, Alberto; Chiurazzi, Pietro; Schornagel, Allan; Serban, Andreea M; van Wijck, Rogier; Cunningham, Janet L; Swagemakers, Sigrid; van der Spek, Peter J
Abrupt onset of severe neuropsychiatric symptoms including obsessive–compulsive disorder, tics, anxiety, mood swings, irritability, and restricted eating is described in children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Symptom onset is often temporally associated with infections, suggesting an underlying autoimmune/autoinflammatory etiology, although direct evidence is often lacking. The pathological mechanisms are likely heterogeneous, but we hypothesize convergence on one or more biological pathways.
Consequently, we conducted whole exome sequencing (WES) on a U.S. cohort of 386 cases, and whole genome sequencing (WGS) on ten cases from the European Union who were selected because of severe PANS. We focused on identifying potentially deleterious genetic variants that were de novo or ultra-rare (MAF) < 0.001.
Candidate mutations were found in 11 genes (PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1) in 21 cases, which included two or more unrelated subjects with ultra-rare variants in four genes. These genes converge into two broad functional categories. One regulates peripheral immune responses and microglia (PPM1D, CHK2, NLRC4, RAG1, PLCG2). The other is expressed primarily at neuronal synapses (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). Mutations in these neuronal genes are also described in autism spectrum disorder and myoclonus-dystonia. In fact, 12/21 cases developed PANS superimposed on a preexisting neurodevelopmental disorder. Genes in both categories are also highly expressed in the enteric nervous system and the choroid plexus.
Thus, genetic variation in PANS candidate genes may function by disrupting peripheral and central immune functions, neurotransmission, and/or the blood-CSF/brain barriers following stressors such as infection.
Web | PDF | Nature Scientific Reports | Open Access
Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders
Cunningham, Janet L; Frankovich, Jennifer; Dubin, Robert A; Pedrosa, Erika; Baykara, Refia Nur; Schlenk, Noelle Cathleen; Maqbool, Shahina B; Dolstra, Hedwig; Marino, Jacqueline; Edinger, Jacob; Shea, Julia M; Laje, Gonzalo; Swagemakers, Sigrid Ma; Sinnadurai, Siamala; Zhang, Zhengdong D; Lin, Jhih-Rong; van der Spek, Peter J; Lachman, Herbert M
INTRODUCTION
Acute onset of severe psychiatric symptoms or regression may occur in children with premorbid neurodevelopmental disorders, although typically developing children can also be affected. Infections or other stressors are likely triggers. The underlying causes are unclear, but a current hypothesis suggests the convergence of genes that influence neuronal and immunological function. We previously identified 11 genes in pediatric acute-onset neuropsychiatric syndrome (PANS), in which two classes of genes related to either synaptic function or the immune system were found. Among the latter, three affect the DNA damage response (DDR): PPM1D, CHK2, and RAG1. We now report an additional 17 cases with mutations in PPM1D and other DDR genes in patients with acute onset of psychiatric symptoms and/or regression that their clinicians classified as PANS or another inflammatory brain condition.
METHODS
We analyzed genetic findings obtained from parents and carried out whole-exome sequencing on a total of 17 cases, which included 3 sibling pairs and a family with 4 affected children.
RESULTS
The DDR genes include clusters affecting p53 DNA repair (PPM1D, ATM, ATR, 53BP1, and RMRP), and the Fanconi Anemia Complex (FANCE, SLX4/FANCP, FANCA, FANCI, and FANCC). We hypothesize that defects in DNA repair genes, in the context of infection or other stressors, could contribute to decompensated states through an increase in genomic instability with a concomitant accumulation of cytosolic DNA in immune cells triggering DNA sensors, such as cGAS-STING and AIM2 inflammasomes, as well as central deficits on neuroplasticity. In addition, increased senescence and defective apoptosis affecting immunological responses could be playing a role.
CONCLUSION
These compelling preliminary findings motivate further genetic and functional characterization as the downstream impact of DDR deficits may point to novel treatment strategies.
Web | PDF | Developmental Neuroscience | Open Access
Conference presentation summarising the above two studies:
Genetics of PANS/PANDAS
Lachman; Frankovich; van der Spek; Cunningham
INTRODUCTION
Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS) is an enigmatic condition characterized by the abrupt onset of obsessive-compulsive disorder (OCD) and/or restricted eating, with two or more secondary symptoms: anxiety, mood lability, rage, cognitive regression, autonomic instability, sensory dysregulation, movement abnormalities, dysuria/enuresis. PANS is believed to be an autoimmune/autoinflammatory disorder that primarily affects basal ganglia. Flares are typically induced by infections, especially group A beta-hemolytic Streptococcus.
METHODS
To understand the pathogenesis of PANS, we carried out two genetic studies. In the first, 391 cases were analyzed by whole exome sequencing (WES), focusing on ultrarare variants (minor allele frequency < 0.0001) in immune and neurodevelopmental disorder (NDD) genes. In the second study, an additional 14 patients had whole WES, and immune and NDD panels were analyzed in 50. We focused primarily on pathogenic ultrarare variants in immune and NDD genes, DNA repair genes, and nuclear genes that affect mitochondrial function.
RESULTS
In the first study, we identified 11 genes (in 21 patients) that code for immune regulators (PPM1D, CHK2, NLRC4, RAG1, and PLCG2) and neuronal function (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, and SGCE). Among the immune genes, PPM1D and CHK2 encode proteins that regulate DNA repair through the p53 DNA damage response (DDR) pathway. NLRC4 codes for an inflammasome component. In the second study, we identified 9 genes in 17 PANS patients. In children with an underlying neurodevelopmental disorder, some flares were more consistent with acute neuropsychiatric regression and seronegative autoimmune encephalitis. The 9 genes clustered around the p53 DDR pathway (PPM1D, ATR, ATM, 53BP1), and members of the Fanconi Anemia Complex (FANCE, FANCI, FANCP, FANCA, FANCC), which also regulate DDR. We also found pathogenic variants in genes that affect mitochondrial function (8 patients; SLC25A5, SLC13A5, TRAK1, MTO1, POLG, PRKN, SPG7, UBR4), and similar to NLRC4, pathogenic variants were found in genes that regulate the innate immune system (13 patients; SAMHD1, LILRA2, OASL, ABL2, DUOX2, RNF215, TNFRSF13B, TLR10). Finally, 10 patients with autism spectrum disorder (ASD) were found to have pathogenic variants in GABBR2, TANC2, ADNP, GRIN2A, and GRIP2. These patients developed acute regression or PANS symptoms similar to our original findings of in patients with SHANK3 and SYNGAP1 mutations.
DISCUSSION/CONCLUSION
These genetic studies show that PANS and regression in ASD are genetically heterogeneous. Yet, our findings suggest convergence on distinct pathways such as inflammasome, toll-like receptor, and NF-kappaB signaling that could impact immunological function if disrupted. The set of genes related to DDR leads to the hypothesis of potential involvement of cGAS-STING, an inducer of type 1 interferons and AIM2 inflammasomes typically activated by viral and bacterial DNA, and damaged nuclear and mitochondrial DNA. We hypothesize that mutations in genes that code for regulators of these pathways increase the risk maladaptive immunological responses and/or neuroinflammation following infections that activate the same pathways. Our findings also suggest that specific genetic subgroups of ASD cases are at increased risk of developing neuropsychiatric decompensation following infections. Confirmations and further characterization of these findings may have translational consequences in PANS and ASD regression in some cases.
As we have discussed before, these terms serve various functions but PANDAS includes disturbances of 'mind' of a sort that I don't think relate to ME/CFS. Some of these things are liste din the first paper SNT quotes. As I understand it these are not just normal emotions reacting to things. People with ME/CFS may be angry but not in a completely inappropriate way.
Yes, if these things occurred after Covid they could be called Long Covid, but that is the problem with Long Covid. IN a sense anyone ill since 2020 has 'Long Covid' if you stretch things - including diabetes, heart attacks and schizophrenia.
We can say that since these seem to be immunological events after infection we can treat tham all the same. But we can do a bit better than that. We know certain events occur after streptococcal infection specifically, others after Herpes infection, and so on, and the dynamics suggest that these are quite unrelated in their immunology.
In terms of classification and usefulness, I think PANDAS is distinct in that it is a concept that includes a causal role for strep.. As indicate,I am unclear that PANS is so helpful, but it implies a role for infection. ME/CFS is a concept that is independent of any role for infection. If we muddle up the type of classification we get into trouble. As indicated,I think Long Covid is increasingly a doubtfully useful term. A lot of it might better be put under old fashioned PVFS.
As we have discussed before, these terms serve various functions but PANDAS includes disturbances of 'mind' of a sort that I don't think relate to ME/CFS. Some of these things are liste din the first paper SNT quotes. As I understand it these are not just normal emotions reacting to things. People with ME/CFS may be angry but not in a completely inappropriate way.
I don't think I've seen all the discussions, but I've seen you refer to psychiatric disorders as disorders of "thought" or something along those lines. Relating to "thoughts" and "mind" is barely a concrete category in my opinion. Anxiety to me feels like the mental version of physical pain - most of the time thoughts are barely involved. I assume you wouldn't refer to chronic pain as psychiatric. But I wouldn't be surprised if the pathophysiology between the two is more similar than between anxiety and bipolar disorder.
My point is we barely know the mechanisms of "mind" or any disorders of "mind". If we barely know the mechanisms of ME/CFS either, I don't think there's any sense in prematurely saying it's unrelated based on this somewhat "top-down" psychological categorization.
As indicate,I am unclear that PANS is so helpful, but it implies a role for infection. ME/CFS is a concept that is independent of any role for infection. If we muddle up the type of classification we get into trouble.
Yet we study "post-infectious ME/CFS". The deep phenotyping study required this criteria. One of the reported loci in DecodeME (OLFM4) was not significant for the whole cohort, but was for ME/CFS following infection.
I just don't see any reason not to study PANS. If we remove the criteria for preceding infection then we're just studying OCD and related disorders, which is already being done. And we never investigate the very small group with OCD following something other than strep and find out if there is some common pathway where any of a number of infections can suddenly switch on OCD.
But we can do a bit better than that. We know certain events occur after streptococcal infection specifically, others after Herpes infection, and so on, and the dynamics suggest that these are quite unrelated in their immunology.
It just seems to me that we don't know enough about the mechanism of OCD to be able to rule out that these unrelated immunological events converge on the same pathway somewhere, just as the unrelated events of Lyme, EBV, COVID, and getting hit in the head might converge somewhere in creating PEM.
Maybe, but I don't think it was a bad idea to at least try lumping everyone in to see if there was any obvious connection between all the presentations, like maybe viral persistence might have panned out.
Ultra-rare variant in CACNA1B found in two siblings with PANS, and the same variant was previously found in a woman with ME/CFS+anorexia.
The ultra-rare variant in CACNA1B, found in two affected siblings (Cases 4 and 5), is a 48 bp insert at the exon 2 splice donor site (c.390 + 1) that is predicted to disrupt splicing. It is part of a set of multiallelic insertion variants, rs370237172, that has an overall MAF of 0.017. However, the 48 bp insert is ultra-rare and has not been observed in control data sets.
We have been unable to genotype the parents. Interestingly, the same 48 bp insert was also identified in a young woman who has been incapacitated with chronic fatigue syndrome (myalgic encephalomyelitis/chronic fatigue syndrome) and anorexia (unpublished observations).
CACNA1B codes for the voltage-dependent N-type calcium channel subunit alpha-1B, a constituent of the Cav2.2 channel. It too is a regulator of synaptic function that acts at the presynaptic terminal to increase neurotransmitter release, which then influences postsynaptic dendritic spine function73.
In addition to having PANS, Case 4 was diagnosed with Hodgkin lymphoma that ultimately required an autologous hematological stem cell transplant (HSCT). It is interesting to note that Hodgkin lymphoma is often found in patients with autoimmune problems and is associated with abnormalities in IL-13 signaling, a cytokine produced by mast cells, eosinophils, nuocytes, and Th2 cells74,75. This patient also has psoriasis, a Th17 associated autoimmune disorder76,77.
This suggests the possibility that CACNA1B could have unrecognized effects on the immune system by disrupting IL-13 and Th17 signaling leading to PANS and an increased risk of hematological malignancy.
Edit: And I don't know how related CACNA1B and CACNA1E are, but the latter was the closest gene to the 23rd most significant locus in DecodeME (p=8.85e-7).
The CACNA1E gene encodes a functionally critical subunit of a high voltage-activated, rapidly inactivating R-type calcium channel which initiates rapid synaptic transmission in the central nervous system (summary by Helbig et al., 2018).
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