Does a Periaqueductal Gray-vagus Nerve Interface Malfunction Explain the Nat hx With Its Numerous Co-morbidities?

Официальное название

(PAG POTS - NIH) Pediatric Postural Orthostatic Tachycardia Syndrome (POTS) : Does a Periaqueductal Gray-vagus Nerve Interface Malfunction Explain the Natural History With Its Numerous Co-morbidities?

Обзор

Postural tachycardia syndrome (POTS) is a common and disabling disorder among adolescents. No epidemiologic data exist to support the often cited 0.5 to 2% prevalence. Case series suggest 3 to 5 times greater incidence in girls than boys. POTS is defined in children as daily chronic symptoms of orthostatic intolerance and a 40 bpm rise in heart rate in the first 10 minutes of a tilt study in the absence of orthostatic hypotension. POTS often develops after an acute event like an illness, infection, immunization, head trauma, psychological trauma or surgery. Natural history data are absent for POTS, though some outcome studies exist. Orthostatic symptoms improve in the majority and heart rate changes improve in 38% at 1 year. A 2-year follow up showed small improvement in comorbid symptoms of POTS in a 12 subject cohort followed yearly. In a pediatric 5-year outcome follow up questionnaire study, 86% of adolescents with POTS reported resolved, improved, or intermittent, symptoms, with primarily physical rather than mental health complaints.

Подробное описание

The current definition of POTS highlights the peripheral mechanistic emphasis of 30 years of studies exploring cardio- and cerebro-vascular, immunologic, mast cell activation, connective tissue and other physiologic mechanisms. The classification of POTS itself also assumes a peripheral etiology, typically including neuropathic, hyperadrenergic, hypovolemic and sometimes immune POTS. However, a central nervous system (CNS) etiology might better account for what is knowns about POTS currently: (1) POTS often follows an infection, physical or psychological trauma. (2) POTS occurs most often in post-menarche adolescent girls volume redistribution differs across subjects (4) exercise, cognitive behavioral therapy provide best long-term outcomes (5) co-morbid disorders, typically overlapping pain conditions such as migraine headache, fibromyalgia, and most functional gastrointestinal disorders (FGID), often dominate the clinical picture. COPCs are typically considered to reflect a CNS etiology.

Because it coordinates the autonomic, motor and pain responses to an acute threat, the midbrain periaqueductal gray region (PAG) is an attractive candidate whose dysfunction could potentially explain all major features of POTS, including the frequent antecedent emotional or physical threat, the POTS core autonomic changes, and the co-morbid pain disorders. The PAG interprets threats as escapable or inescapable, specifically activating a different column for each response type.

Вмешательства

• Поведенческое Questionnaires to be competed
  * The Pain Coping Questionnaire short form * Functional Disability Inventory (FDI), the primary clinical outcome measure. * COMPASS-31 and orthostatic hypotension modified for POTS. * The Pain Response Inventory (PRI)PROMIS Depression * GAD-7 for anxiety * Varni/Thompson Pediatric Pain Questionnaire * Child and Parent Reports of Post-Traumatic Symptoms (CROPS/PROPS) * Pain Catastrophizing Scale (PCS-C) * Detailed account of natural history and evolution of POTS and COPCs through MEDYSA (facilita
• Поведенческое Provide list of medication and lifetime events
  Participants will provide a list of all medications taken at each visit time, lifetime history of infections, traumas, and other significant life events.
• Поведенческое Use phone App to record new life events
  Subjects will also record new life events, minor traumas, entrance into a flare and menses in Ilumivu's EMA (Ecological Momentary Assessment) phone App
• Устройство Will wear an activity monitor
  Participants will have an activity monitor loaned for the duration of the study to track their physical activity.
• Другое Periodic 24-hour urine sodium check
  POTS patients will have a periodic 24-hour urine sodium check to determine compliance to intake of salt.
• Диагностический тест A fMRI scan
  • Participants will complete a fMRI scan without contrast and complete a looming animacy threat task; participants judge the valence of images via button press as they perceive the image.
• Диагностический тест A bedside tilt test will be performed
  A bedside tilt test will be performed where blood pressure will be recorded supine and upright positions to confirm/exclude POTS.
• Другое IV placed to collect blood samples
  • An IV will be place for collection of 4 blood samples, about 12 mL of blood. For each position (lying and standing) the study team will draw 2 tubes each times with 3 mL of blood, for a total of 4 lab tubes (12 mL). Physical exams to assess the 18-tender points described by the American College of Rheumatology for the diagnosis of fibromyalgia and hypermobility/Ehlers-Danlos Syndrome (EDS) exam will be performed in all subjects.
• Другое Stool Sample
  • Participants will provide a stool biospecimen sample at each in-person visit. Stool will be collected in a hat and sample will be swabbed with the swab placed directly into PrimeStore collection tube and the remainder of the sample discarded

Первичные конечные точки

• Functional Disability Inventory (FDI) [Срок оценки: Experimental Cohort: Baseline and monthly for 24 months (3, 6, 12, 24 in-person study visits), the other months will be completed from home. The control cohort: months 0-12]
• Pain Coping Questionnaire short form [Срок оценки: Experimental Cohort: Baseline and monthly for 24 months (3, 6, 12, 24 in-person study visits), the other months will be completed from home. The control cohort: months 0-12]
• Pain Catastrophizing Scale (PCS-C) [Срок оценки: Experimental Cohort: Baseline and monthly for 24 months (3, 6, 12, 24 in-person study visits), the other months will be completed from home. The control cohort: months 0-12]
• Functional MRI (fMRI) scan while completing a complete a looming animacy threat task; participants judge the valence of images via button press as they perceive the image. [Срок оценки: Experimental cohort: Baseline, 3, 6, 12, 24 month in person visits. Control Cohort: Baseline, 3, 6, and 12 month in person visits.]
• Bedside Tilt test [Срок оценки: Experimental cohort: Baseline, 3, 6, 12, 24 month in person visits. Control Cohort: Baseline, 3, 6, and 12 month in person visits.]

Критерии участия

POTS sample

Критерии включения

• symptomatic ≥ 40 bpm rise in heart rate in the first 10 min of a tilt table study without a drop in blood pressure
• Clinical symptoms of orthostatic intolerance

Критерии исключения

• Pregnant or breastfeeding
• Cognitive defects that preclude answering questionnaires or following assessment directions
• Other chronic diseases
• Unstable medical conditions
• Use of narcotics
• Limited English proficiency
• Investigator discretion that participant would not be suitable to participate
• A phone older than 5 years old or unable to support EMA software

POST INFECTION

Критерии включения

• acute upper respiratory or gastrointestinal infection that required admission to the acute care units but not requiring an ICU stay

Критерии исключения

• Pregnant or breastfeeding
• Chronic prescriptions, history of POTS or orthostatic symptoms, recent inpatient psychiatric admissions, substance use disorder, trauma such as a motor vehicle accident, surgery, or other significant physical or emotional trauma in the last 5 years
• Cognitive defects that preclude answering questionnaires or following assessment directions
• Other unstable chronic diseases
• Unstable medical conditions
• Use of narcotics
• Severe depression or anxiety (untreated / unstable)
• Limited English proficiency
• Investigator discretion that participant would not be suitable to participate
• A phone older than 5 years old or unable to support EMA software

HEALTHY CONTROLS

Критерии включения

• Apparently healthy with no known chronic illnesses

Критерии исключения

• Pregnant or breastfeeding
• History of POTS or orthostatic symptoms, migraines, fibromyalgia, chronic fatigue, PTSD. Functional gastrointestinal disorders, fainting, dysmenorrhea, or other chronic pain syndrome, inpatient psychiatric admissions, substance use disorder, trauma such as a motor vehicle accident, surgery, or other significant physical or emotional trauma in the last 5 years
• Cognitive defects that preclude answering questionnaires or following assessment directions
• Other chronic unstable diseases
• Unstable medical conditions
• Use of narcotics
• Severe depression or anxiety (untreated / unstable)
• Limited English proficiency
• Investigator discretion that participant would not be suitable to participate
• A phone older than 5 years old or unable to support EMA software

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

США · 1 центр

• Virginia Commonwealth University — Richmond

Идентификаторы

NCT: NCT06616363 · HM20029682 · 1R01HL163577

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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