Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS) are immunologically mediated conditions characterized by abrupt-onset obsessive-compulsive behaviors and a range of complex neuropsychiatric symptoms (Swedo et al., 2012; Frankovich et al., 2015; Vreeland et al., 2023). First described by Swedo et al. (2012), these disorders are increasingly recognized as post-infectious syndromes potentially involving autoantibodies against basal ganglia structures (Swedo et al., 2012; Frankovich et al., 2015; Vreeland et al., 2023). PANDAS, in particular, is classically triggered by Group A Streptococcal (GAS) infection, while PANS encompasses a broader array of potential triggers including viral infections, neuroinflammation, metabolic dysregulation, and endocrine perturbations (Lojek and Rzeszutek, 2025).

Clinically, PANS is defined by the sudden onset of obsessive-compulsive symptoms or restrictive eating accompanied by at least two additional neuropsychiatric features. These often include anxiety, tics, mood instability, irritability, aggression, sensory abnormalities, and cognitive regression (Swedo et al., 2012; Frankovich et al., 2015). Importantly, somatic symptoms such as enuresis, mydriasis, and notably, sleep disturbances, are also common (Swedo et al., 2012; Frankovich et al., 2015; Vreeland et al., 2023). Despite this, objective investigations of sleep in PANS remain scarce, with a dearth of data using polysomnography (PSG; also see Table 1).

Emerging literature has highlighted sleep abnormalities as a core, yet under-investigated, feature of PANS. Chang et al. (2015) and Swedo et al. (2012) reported that up to 84% of PANS patients experience sleep-related complaints including insomnia, parasomnias, nightmares, and sleep fragmentation. Recent studies using PSG have identified specific disturbances in REM sleep, particularly REM sleep without atonia (RSWA) and REM sleep behavior disorder (RBD), suggesting a potential dysfunction in brainstem and subcortical REM regulatory circuits (Table 1).

Gaughan et al. (2016) conducted one of the earliest PSG-based studies in this population and reported that 87% of children with active PANS symptoms had at least one REM sleep abnormality, including 27% who met full RBD criteria and 53% who exhibited REM motor disinhibition. These findings were corroborated by Santoro et al. (2018), who found elevated periodic limb movement indices (PLMI) in 78% of their PANS sample and identified RSWA in several patients upon manual scoring. Similarly, Gagliano et al. (2021) reported that 74% of PANS patients displayed at least one PSG abnormality, with 65% exhibiting RSWA and 47% meeting criteria for periodic limb movement disorder (PLMS). These studies collectively demonstrate that REM-related motor disinhibition could be considered a recurrent and quantifiable feature in PANS.

A more recent investigation Congiu et al. (2024) further substantiated these findings using the REM Atonia Index (RAI), a validated PSG metric for quantifying RSWA. In a sample of 69 children with PANS and 44 age- and sex-matched controls, the RAI was found significantly lower in the PANS group, with 25 PANS subjects showing pathological REM atonia levels compared to only one control, perhaps again in support of the potential of RSWA as a biomarker of central neuroinflammatory involvement in PANS.

Notably, a case report by Congiu et al. (2024) described a child with concurrent narcolepsy type 1 (NT1) and PANS, arguing for a shared immunological spectrum. Wenz et al. (2023) similarly described three children diagnosed with both NT1 and Sydenham's chorea, reinforcing the hypothesis that post-infectious autoimmune disorders may converge upon common neurobiological pathways affecting REM regulation (Figure 1).

Traditionally, several models have been proposed to explain REM sleep abnormalities in PANS. Neuroimaging studies and serological findings consistently demonstrate basal ganglia involvement, including autoantibody targeting of dopamine D1 and D2 receptors, tubulin, and lysoganglioside GM1 (Frankovich et al., 2015; Vreeland et al., 2023). These autoantibodies may interfere with cortico-striato-thalamo-cortical loops and disrupt projections to brainstem nuclei responsible for REM atonia (Figure 1). Furthermore, basal ganglia and thalamic inflammation may alter downstream activity in the sublaterodorsal tegmental nucleus and medullary inhibitory centers that regulate muscle tone during REM sleep (Figure 1).

Dopaminergic dysfunction is another likely contributor. Dopamine modulates motor inhibition and arousal, and its dysregulation is associated with both RBD and PLMS (Drakatos et al., 2021; Wasserman et al., 2021). Inflammatory insult to dopaminergic circuits in PANS may, thus, arguably, simultaneously act to produce tics, executive dysfunction, and REM disinhibition. Supporting this view, iron deficiency, a common metabolic finding in PANS, impairs tyrosine hydroxylase activity, reducing dopamine synthesis and compounding sleep-related motor instability (Drakatos et al., 2021; Daubner et al., 2011).

Another putative player in REM modulation could be the orexin (hypocretin) system. Orexin neurons, located in the lateral hypothalamus, orchestrate arousal, REM transitions, and maintenance of muscle atonia through projections to the brainstem (Concetti and Burdakov, 2021). Orexin deficiency is the hallmark of NT1, and partial orexin dysregulation may result in fragmented REM and RSWA without full narcoleptic features (Antelmi et al., 2020). Emerging evidence from preclinical studies suggests that chronic inflammation may activate a reserve population of orexin-expressing neurons in a compensatory, yet dysregulated, manner, leading to hyperarousal and REM sleep instability (James and Aston-Jones, 2022; Clark and Vissel, 2014). This concept may be particularly relevant to PANS, where immune dysregulation, stress, and fluctuating orexin tone may underlie overlapping features with NT1.

Importantly, while RSWA (when accompanied with dream re-enactment) is well-recognized as a harbinger of neurodegeneration in synucleinopathies (Högl et al., 2018), its presence in pediatric autoimmune conditions such as PANS may reflect a reversible, functional disturbance. Observational studies have shown that RSWA and related PSG abnormalities may improve with immunotherapy, including corticosteroids and intravenous immunoglobulin (IVIG), suggesting that sleep phenotyping could serve as a treatment-responsive biomarker.

In light of these findings, we undertook a critical literature synthesis on sleep disturbances in PANS and presents a novel adult case of persistent RSWA (see Table 1). To our knowledge, this is the first documented case of an adult with longstanding PANS exhibiting polysomnographically confirmed RSWA. We propose a mechanistic model in which basal ganglia autoimmunity, dopaminergic and orexinergic dysregulation, and inflammatory stress converge to impair REM motor control. By extending our understanding of REM pathology beyond degenerative contexts, we advocate for the integration of sleep evaluation into the diagnostic framework for PANS and related neuroimmune syndromes.

This case offers novel insight into the neurobiological mechanisms underpinning REM sleep abnormalities in Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), particularly REM Sleep Without Atonia (RSWA), by presenting the first known adult case with longstanding PANS exhibiting persistent RSWA on polysomnography. It raises key questions regarding the underlying pathophysiology of sleep regulation in PANS and provides a conceptual framework to understand how chronic neuroinflammation, basal ganglia dysfunction, and orexinergic dysregulation may intersect to produce motor disinhibition during REM sleep.

RSWA, characterized by abnormal muscle tone during REM sleep, is traditionally associated with REM Sleep Behavior Disorder (RBD) and is considered an early marker for neurodegenerative diseases, such as Parkinson's disease and dementia with Lewy bodies (Högl et al., 2018). However, in inflammatory or autoimmune contexts, RSWA may reflect transient or reversible dysfunction in REM atonia pathways. This is increasingly supported by observations in pediatric cohorts with PANS/PANDAS, where high rates of RSWA and RBD-like features have been detected without evidence of neurodegeneration (Gaughan et al., 2016; Santoro et al., 2018; Gagliano et al., 2021; Congiu et al., 2024).

The central hypothesis supported by this case is that immune-mediated neuroinflammation, particularly affecting the basal ganglia, thalamus, and brainstem REM regulatory nuclei, disrupts motor inhibition during REM sleep (Figure 1). Neuroimaging and serological studies in PANS frequently indicate inflammatory lesions in these regions, with a strong emphasis on basal ganglia involvement (Swedo et al., 2012; Frankovich et al., 2015). Autoantibodies targeting dopamine receptors (D1, D2), tubulin, and lysoganglioside-GM1 have been consistently identified in patients with PANS and Sydenham's chorea, another post-streptococcal autoimmune disorder (Vreeland et al., 2023). These antibodies may disrupt striatal-thalamocortical loops and interfere with inhibitory control of motor outputs during REM sleep.

As mentioned, dopaminergic dysfunction likely plays a pivotal role. The substantia nigra and ventral tegmental area (VTA), key dopaminergic hubs, project to both limbic and motor regions and modulate REM sleep via downstream connections to pontine reticular structures (Liu et al., 2020). Inflammatory interference with these circuits could explain co-occurring features such as tics, cognitive dysfunction, mood lability, and REM dysregulation (Figure 1). The frequent finding of periodic limb movements during REM (PLMS) in PANS further implicates dysregulated dopamine synthesis and signaling, as PLMS is well-known to respond to dopaminergic therapies and is often associated with iron deficiency (Gagliano et al., 2021; Drakatos et al., 2021).

Indeed, iron metabolism might be an underappreciated factor in the pathophysiology of REM abnormalities in PANS. Iron is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis (Daubner et al., 2011). Low ferritin levels have been repeatedly observed in PANS cohorts and, in conjunction with immune activation, may create a neurochemical milieu that is permissive for motor instability during REM (Santoro et al., 2018). This metabolic vulnerability may further destabilize cortico-striatal-thalamocortical loops and dopaminergic tone.

More recently, the possible role of the orexin system in PANS and sleep regulation has come into focus (Congiu et al., 2024; Knez et al., 2022). Orexin neurons, located in the lateral hypothalamus, are essential for maintaining wakefulness, regulating REM transitions, and enforcing REM muscle atonia via their projections to pontine inhibitory centers (Concetti and Burdakov, 2021). Loss of orexin-producing neurons is the defining feature of narcolepsy type 1 (NT1), which presents with RSWA, cataplexy, and disrupted REM control (Antelmi et al., 2020). Although CSF orexin levels were not measured in this case, the clinical overlap with NT1 raises the possibility of partial orexinergic dysregulation.

Preclinical studies have introduced the concept of an “orexin reserve,” a subpopulation of dormant or immature orexin-expressing neurons that can be recruited during high arousal, stress, or inflammation (James and Aston-Jones, 2022). Clark and Vissel (Clark and Vissel, 2014) suggest that under chronic neuroimmune stress, these reserve neurons may be pathologically activated, leading to a state of heightened arousal and impaired REM inhibition. In PANS, ongoing immune activation, cytokine release, and possible hypothalamic inflammation could activate these reserve circuits, producing hyperarousal, insomnia, and RSWA in the absence of complete orexin neuron loss (Figure 1).

This model is particularly relevant in light of the co-occurrence of PANS with narcolepsy and other sleep-related autoimmune disorders. Congiu et al. (2024) described a child with both NT1 and PANS, and Wenz et al. (2023) reported cases with overlapping NT1 and Sydenham's chorea. These findings support notion that post-infectious autoimmune conditions may affect shared sleep-regulating neural networks, particularly those involving orexin and dopamine.

In the reported case in our study, the patient has never received corticosteroids, intravenous immunoglobulin (IVIG), or other immunomodulatory treatments, however, existing literature suggests that REM sleep abnormalities in PANS may be responsive to such therapies (Swedo et al., 2012). Observational reports indicate that sleep parameters, including RSWA, may improve in tandem with clinical recovery following immune-targeted interventions (Frankovich et al., 2015). Thus, further evaluation of immunomodulatory approaches in this case may provide insights into the reversibility of REM dysfunction.

From a diagnostic standpoint, the presence of RSWA and REM fragmentation in PANS should prompt clinicians to consider a broader differential diagnosis that includes neuroimmune and sleep regulatory dysfunctions. Currently, sleep abnormalities in PANS are often under-recognized or misattributed to psychiatric comorbidities. We suggest that standardized PSG evaluation and REM Atonia Index (RAI) quantification could provide objective biomarkers of disease activity and treatment response.

In this particular case, the patient was reassured with findings, and at that present time, reluctant to engage in further treatment or follow up. A pragmatic plan in case of change of the clinical presentation was presented including a repeat vPSG within 3–6 months, with the same montage, and RSWA quantification, as objective outcome measures. Moreover, it was proposed to monitor iron status, and to consider corrections if ferritin < 75 μg/L, given dopamine/PLMS links. Furthermore, recommendation for potential additional behavioral sleep interventions were similarly considered (for instance sleep scheduling, stimulus control, or cognitive behavioral therapy for insomnia (CBT-I), if indicated). Clinically, immunomodulation should be considered by clinicians, if clinical and laboratory criteria support an inflammatory flare. Ideally, multi-disciplinary approach should be followed with sleep physicans documenting pre/post-treatment RSWA/RAI as response biomarkers.

Importantly, this case contributes to the growing body of evidence that PANS can persist into adulthood (Bodner et al., 2001; Deshmukh et al., 2022), challenging the notion that it is strictly a pediatric disorder. Presently due to the scarcity of the reports in the literature it is difficult to gauge any potential differences in pediatric vs. adult phenotype. As discussed, pediatric cohorts with PANS appear to include REM-related motor disinhibition on vPSG, including elevated RSWA/low RAI and REM-periodic limb movements (see Table 1). The present case demonstrates persistence of RSWA into early adulthood, despite otherwise normal respiratory indices and low PLMI, extending the pediatric observations into the adult spectrum. This supports the working hypothesis that in PANS, REM atonia circuitry could be chronically susceptible to immune-mediated dysregulation beyond childhood. In future it would be of interest to investigate adult patients presenting with treatment-resistant OCD, tics, and sleep disturbances, and to screen them for a history of acute-onset symptoms and infection-related relapses. Our patient, who continued to experience RSWA years after disease onset, exemplifies the need for longitudinal follow-up and continued research into the chronicity and progression of PANS.

There are several important limitations to this case, including the absence of CSF orexin measurement and neuroimaging markers specific to inflammation. However, the reported temporal association of immune flares with symptom recurrence, the documented PSG findings, and the immune-responsive pattern of symptom recurrence, provide strong, if circumstantial, evidence for an immune-mediated REM sleep phenotype. Future studies should integrate multimodal imaging, serum and CSF autoantibody profiling, and longitudinal PSG to better delineate the pathophysiology and treatment response in PANS.

In conclusion, this case supports a mechanistic model in which chronic neuroinflammation, basal ganglia-autoantibody interference, dopaminergic disruption, and orexinergic dysregulation coalesce to produce REM sleep disinhibition in PANS. RSWA in this context is not merely a parasomnia but may represent a key physiological marker of CNS inflammation. As such, sleep phenotyping should be incorporated into clinical evaluations and research frameworks for PANS and other neuroimmune disorders.