BIOMA-PANS - Diagnostic and Treatment-response BIOMArkers in Children and Adolescents With PANS (Pediatric Acute-onset Neuropsychiatric Syndrome)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 80
- 试验地点
- 5
- 主要终点
- The primary outcome is the xperimental demonstration that the effects of inflammatory response in CNS is represented by the behavioral and cognitive changes and sleep alterations typically found in PANS.
研究概览
简要总结
Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a complex neuropsychiatric disorder characterized by the abrupt onset of symptoms and currently diagnosed mainly on clinical criteria, as reliable diagnostic biomarkers are still lacking. The primary objective of this project is to identify and validate a panel of neurophysiological, molecular, genetic, and metabolomic biomarkers associated with disease onset, clinical trajectory, and response to antimicrobial, anti-inflammatory, and immunomodulatory treatments. Identifying objective biomarkers will improve diagnostic accuracy, facilitate earlier diagnosis, clarify disease mechanisms, and support the development of more targeted therapeutic strategies.
PANS is currently considered a multifactorial immune-mediated inflammatory brain disorder resulting from the interaction of genetic susceptibility, immune dysregulation, infections, and environmental factors such as stress or trauma. Current evidence suggests that both innate and adaptive immune responses contribute to disease pathophysiology through interactions between the peripheral immune system and the central nervous system.
The pathogenic process may begin during fetal life through Maternal Immune Activation (MIA), whereby maternal infections or immune dysregulation induce inflammatory responses that increase susceptibility to neurodevelopmental disorders. During the postnatal period, infectious agents, including viruses, Mycoplasma pneumoniae, and Haemophilus influenzae, may trigger immune activation, leading to blood-brain barrier disruption, glial activation, and abnormalities within cortico-basal ganglia circuits thought to underlie PANS symptoms.
To achieve these objectives, the project will adopt a multidisciplinary translational approach that combines the enrolment and characterization of pediatric patients with PANS with complementary studies in animal models. Particular emphasis will be placed on clinical and sleep features, together with molecular and metabolomic profiling, to identify biomarkers with diagnostic and prognostic value and to investigate the biological pathways underlying disease onset and progression.
Given the high clinical, social, and economic burden of PANS, which frequently follows a chronic or relapsing-remitting course requiring long-term healthcare support, earlier diagnosis and a better understanding of disease mechanisms could significantly improve patient management. More broadly, the project will contribute to understanding the immune-mediated pathogenic pathways underlying PANS and related neurodevelopmental disorders, supporting the transition from symptom-based classification toward mechanism-based diagnosis and treatment.
详细描述
The specific aim 1 is the Neurophysiological and clinical characterization of sleep and Electroencephalographic (EEG) patterns. This aim focuses on the systematic characterization of sleep architecture and EEG features in pediatric patients with Pediatric Acute Neuropsychiatric Syndrome (PANS), a domain that remains largely unexplored despite growing clinical evidence of sleep disturbances in this population. Preliminary reports and consensus guidelines suggest the presence of nonspecific EEG abnormalities, including focal or generalized slowing and, less frequently, epileptiform activity. However, no structured, systematic evaluation has been conducted to define their prevalence, clinical correlates, and longitudinal evolution.
Polysomnographic studies in PANS suggest a high burden of sleep disturbances, including insomnia, parasomnias, periodic limb movement disorder, and Rapid Eye Movement stage (REM) sleep abnormalities such as REM sleep without atonia and REM behavior disorder. These alterations may contribute to daytime cognitive dysfunction, attentional deficits, fatigue, and "brain fog," which are commonly reported in affected children. All enrolled patients will undergo standardized overnight polysomnography and EEG recording at baseline and after treatment. Sleep architecture, respiratory parameters, limb movements, and EEG activity will be analyzed according to American Academy of Sleep Medicine (AASM) criteria. The aim is to define objective neurophysiological markers associated with disease severity and clinical symptom clusters.
A cohort of at least 50 pediatric patients (3-18 years) with a clinical diagnosis of PANS will be recruited at the Child and Adolescent Neuropsychiatry Unit of the Azienda Ospedaliero Universitaria (AOU) Policlinico "G. Martino" in Messina. Diagnosis will be confirmed independently by two child neuropsychiatrists according to established consensus criteria. Clinical characterization will include standardized assessments of symptom severity and functioning, including psychometric scales, and cognitive evaluation using age-appropriate intellectual evaluation through the Wechsler scales. A detailed clinical history will be collected, including the disease course, infectious triggers, autoimmune comorbidities, family history, and treatment response.
A control group of at least 30 age- and sex-matched neurotypical subjects will be enrolled. Exclusion criteria include major medical, neurological, or psychiatric conditions and current immunomodulatory treatments.
All participants will undergo comprehensive laboratory screening to exclude systemic conditions and will be evaluated using standardized cognitive and neuropsychological batteries. Sleep assessment will include a clinical interview, overnight polysomnography, and a standard EEG recording, all performed within the same week as the clinical evaluation. Sleep scoring will follow AASM criteria and will be conducted by experienced sleep medicine specialists. Data from clinical, neuropsychological, neurophysiological, genetic, and molecular assessments will be integrated into a unified database for multilevel correlation analyses.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 3 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •(I) PANS diagnosis made according to 2010 NIH criteria
排除标准
- •(for the PANS group):
- •(I) onset of specific rheumatologic or immunologic diseases;
- •(II) presence of a diagnosed cancer or other severe medical illnesses;
- •(III) active treatment with steroidal or non-steroidal anti-inflammatory drugs
- •The control group must include children without autoimmune diseases, neurodevelopmental or psychiatric disorders, and with adequate academic performance and functional level.
研究组 & 干预措施
PANS group
Children and adolescents diagnosed with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) undergoing clinical, neurophysiological, genetic, metabolomic, miRNA and sleep assessments.
干预措施: Psycodiagnostic evaluation (Diagnostic Test)
PANS group
Children and adolescents diagnosed with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) undergoing clinical, neurophysiological, genetic, metabolomic, miRNA and sleep assessments.
干预措施: Polysomnography (Diagnostic Test)
PANS group
Children and adolescents diagnosed with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) undergoing clinical, neurophysiological, genetic, metabolomic, miRNA and sleep assessments.
干预措施: 1H-NMR analysis (Diagnostic Test)
PANS group
Children and adolescents diagnosed with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) undergoing clinical, neurophysiological, genetic, metabolomic, miRNA and sleep assessments.
干预措施: miRNA sequencing (Diagnostic Test)
Healthy Controls
Age- and sex-matched neurotypical children without autoimmune, neurodevelopmental or psychiatric disorders undergoing the same assessment protocol for comparison.
干预措施: Psycodiagnostic evaluation (Diagnostic Test)
Healthy Controls
Age- and sex-matched neurotypical children without autoimmune, neurodevelopmental or psychiatric disorders undergoing the same assessment protocol for comparison.
干预措施: Polysomnography (Diagnostic Test)
Healthy Controls
Age- and sex-matched neurotypical children without autoimmune, neurodevelopmental or psychiatric disorders undergoing the same assessment protocol for comparison.
干预措施: 1H-NMR analysis (Diagnostic Test)
Healthy Controls
Age- and sex-matched neurotypical children without autoimmune, neurodevelopmental or psychiatric disorders undergoing the same assessment protocol for comparison.
干预措施: miRNA sequencing (Diagnostic Test)
结局指标
主要结局
The primary outcome is the xperimental demonstration that the effects of inflammatory response in CNS is represented by the behavioral and cognitive changes and sleep alterations typically found in PANS.
时间窗: From the enrollment through study completion, an average of 36 months
This outcome aims to corroborate the current evidence on the neuroinflammatory substrate of PANS. Starting from the assumption that brain inflammatory reactions may promote the development of neuropsychiatric symptoms, the study is aimed to enhance the knowledge on the role of specific inflammatory pathways able to deteriorate the neurocircuitry and neurotransmitter systems. Thus, the first expected outcome of this study is the experimental demonstration that the effects of inflammatory response in CNS is represented by the behavioral and cognitive changes typically found in PANS, as well as other neurodevelopmental and psychiatric disorders. In fact, PANS represents the prototypical feature of psychiatric symptoms occurring as a result of an inflammatory state of the CNS. Overcoming the rigid categorical approach, PANS can be seen as one of the possible phenotypic manifestations of the complex pathogenic pathways leading to neurodevelopmental disorders and psychiatric symptoms.
Concentrations of predefined inflammatory biomarkers
时间窗: From the enrollment through study completion, an average of 36 months
Inflammatory biomarker concentrations will be measured in biological samples using predefined laboratory assays. Associations between biomarker concentrations and psychiatric, neuropsychological, and polysomnographic measures will be evaluated using predefined statistical analyses.
次要结局
- Identification of molecular mechanisms and biological signatures(From the biological samples collection to the end of analysis, an average of 2 years)
- Development of a translational model(from the start of the study to the first year)
- Identification of biomarkers and future therapeutic implications(From the enrollment From the enrollment through study completion, an average of 36 months)
- Expression levels of selected microRNAs(From the biological samples collection to the end of analysis, an average of 2 years)
- Metabolomic profile(From the biological samples collection to the end of analysis, an average of 2 years)
- Frequency of pathogenic and likely pathogenic genetic variants(From the biological samples collection to the end of analysis, an average of 2 years)
- Molecular signatures in the maternal immune activation model(From the biological samples collection to the end of analysis, an average of 2 years)
- Diagnostic performance of candidate biomarkers(From enrollment through study completion (approximately 36 months))
研究者
Monica Puligheddu
Prof.
University of Cagliari