Creating a data dictionary for pediatric autonomic disorders.

PURPOSE: Whether evaluating patients clinically, documenting care in the electronic health record, performing research, or communicating with administrative agencies, the use of a common set of terms and definitions is vital to ensure appropriate use of language. At a 2017 meeting of the Pediatric Section of the American Autonomic Society, it was determined that an autonomic data dictionary comprising aspects of evaluation and management of pediatric patients with autonomic disorders would be an important resource for multiple stakeholders. METHODS: Our group created the list of terms for the dictionary. Definitions were prioritized to be obtained from established sources with which to harmonize. Some definitions needed mild modification from original sources. The next tier of sources included published consensus statements, followed by Internet sources. In the absence of appropriate sources, we created a definition. RESULTS: A total of 589 terms were listed and defined in the dictionary. Terms were organized by Signs/Symptoms, Triggers, Co-morbid Disorders, Family History, Medications, Medical Devices, Physical Examination Findings, Testing, and Diagnoses. CONCLUSION: Creation of this data dictionary becomes the foundation of future clinical care and investigative research in pediatric autonomic disorders, and can be used as a building block for a subsequent adult autonomic data dictionary.

Patient-Centered Paradigm for Managing Autonomic Long COVID Symptoms During Sports and Exercise.

ABSTRACT: This report highlights a new, patient-centered paradigm for managing post-COVID-19 dysautonomia symptoms during sports and exercise. The patient was a healthcare worker exposed before vaccination. She experienced postural orthostatic tachycardia plus exertional tachycardia, with postexertional fatigue, beginning a few weeks after testing positive for COVID-19. Stress test, echo, and an extensive dysautonomia evaluation were negative. Recommended nonpharmacological and pharmacological interventions were poorly tolerated. Prescription of a novel regimen of "basal-dose" ivabradine, plus very low-dose metoprolol according to an exertional "sliding scale" managed symptoms to an acceptable level for work and recreation.

Inappropriate sinus tachycardia: a review.

Inappropriate sinus tachycardia (IST) has been defined as a resting heart rate of >100 beats per minute and an average 24-hour heart rate >90 bpm with distressing symptoms resulting from the persistent tachycardia. IST is prevalent in 1% of the middle-aged population, mostly females. Rarely can elderly patients also present with IST. Possible mechanisms of IST include intrinsic sinus node abnormality, beta-adrenergic receptor stimulating autoantibody, beta-adrenergic receptor supersensitivity, muscarinic receptor autoantibody, or hyposensitivity, impaired baroreflex control, depressed efferent parasympathetic/vagal function, nociceptive stimulation, central autonomic overactivity, aberrant neurohumoral modulation, etc. Symptoms associated with IST are palpitations, chest pain, fatigue, shortness of breath, presyncope, and syncope. Despite these distressing symptoms, IST has not been associated with tachycardia-associated cardiomyopathy or increased major cardiovascular events. Various treatment options for patients with IST are ivabradine, beta-adrenergic blockers, calcium channel blockers, psychiatric evaluation, and exercise training. Although, endocardial radiofrequency ablation targeting the sinus node has been used as a treatment modality for otherwise treatment-refractory IST, the results have been dismal. The other modalities used for refractory IST treatment are endocardial modification of the sinus node using radiofrequency energy, combined endo and epicardial ablation of the sinus node, thoracoscopic epicardial ablation of the sinus node, sinus node sparing thoracoscopic and endocardial hybrid ablation. The goal of this review is to provide the readership with the pathophysiological basis of IST and its management options.

Management strategies for vasovagal syncope.

Vasovagal syncope (VVS) (or neurocardiogenic syncope) is a common clinical condition that is challenging to both physicians and patients alike. Severe episodes of recurrent syncope can result in physical injury as well as psychological distress. This article provides a brief overview of current management strategies and a detailed overview of therapeutic modalities such as closed loop stimulation (CLS) and cardioneuroablation (CNA).

Risks of adverse events in patients with orthostatic intolerance undergoing surgery with general anesthesia.

INTRODUCTION: Orthostatic intolerance (OI) is a group of disorders characterized by symptoms that occur upon standing and resolve with recumbence. Although well established but not widely recognized, these diagnoses may create uncertainty for clinicians dealing with a patient affected by OI and requiring a surgical procedure. OBJECTIVES: To determine the rate of intra- and postoperative major adverse events in patients with OI undergoing surgery with general anesthesia. METHODS: The study was a retrospective study of patients with orthostatic intolerance who underwent surgery requiring general anesthesia from 1 January 2000 to 31 December 2018. RESULTS: A total 171 patients with OI underwent 190 surgeries. In patients with POTS and orthostatic-induced VVS, there were no major significant adverse events. There was one episode of AVNRT in a patient with POTS and one episode of bradycardia secondary to vasovagal reflex in a patient with orthostatic-induced VVS. Moreover, there were 13 (6.8%) episodes of postoperative hypotension. However, the majority of these episodes were related to bleeding, volume depletion or sepsis. All cases of hypotension responded well to appropriate therapy. In patients with OH, the rate of postoperative major adverse cardiac events was 4.7%, and the 30-day mortality rate was 6.1%. This is not significantly different from the calculated risk for patients without OH. There were no myocardial infarctions or deaths at 30 days in patients with POTS or orthostatic-induced VVS. CONCLUSION: Patients with OI may not experience higher rates of perioperative complications compared with patients without OI syndromes.

TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization.

Transient receptor potential ankyrin 1 (TRPA1) plays a role in migraine and is proposed as a promising target for migraine therapy. However, TRPA1-induced signaling in migraine pathogenesis is poorly understood. In this study, we explored the hypothesis that Src family kinases (SFKs) transmit TRPA1 signaling in regulating cortical spreading depression (CSD), calcitonin gene-related peptide (CGRP) release and neuroinflammation. CSD was monitored in mouse brain slices via intrinsic optical imaging, and in rats using electrophysiology. CGRP level and IL-1ß gene expression in mouse trigeminal ganglia (TG) was detected using Enzyme-linked Immunosorbent Assay and Quantitative Polymerase Chain Reaction respectively. The results showed a SFKs activator, pYEEI (EPQY(PO3H2)EEEIPIYL), reversed the reduced cortical susceptibility to CSD by an anti-TRPA1 antibody in mouse brain slices. Additionally, the increased cytosolic phosphorylated SFKs at Y416 induced by CSD in rat ipsilateral cerebral cortices was attenuated by pretreatment of the anti-TRPA1 antibody perfused into contralateral ventricles. In mouse TG, a SFKs inhibitor, saracatinib, restored the CGRP release and IL-1ß mRNA level increased by a TRPA1 activator, umbellulone. Moreover, umbellulone promoted SFKs phosphorylation, which was reduced by a PKA inhibitor, PKI (14-22) Amide. These data reveal a novel mechanism of migraine pathogenesis by which TRPA1 transmits signaling to SFKs via PKA facilitating CSD susceptibility and trigeminovascular system sensitization.

Ivabradine in children with postural orthostatic tachycardia syndrome: a retrospective study.

BACKGROUND: Ivabradine is a unique medication that reduces the intrinsic heart rate by specifically blocking the inward funny current that controls the pacemaker activity of the sinus node. We conducted a retrospective cohort study to assess the efficacy of ivabradine in children suffering from postural orthostatic tachycardia syndrome. METHODS: A chart review was conducted of patients less than 18 years of age who were diagnosed with postural orthostatic tachycardia syndrome who had received ivabradine as treatment from January 2015 to February 2019 at our institution. Twenty-seven patients (25 females, 92.5%) were identified for the study. The outcomes which were assessed included a change in the severity and frequency of symptoms, heart rate, and blood pressure before and after starting ivabradine. RESULTS: There was an improvement in the symptoms of 18 (67%) out of 27 patients. The most notable symptom affected was syncope/presyncope with a reduction in 90%, followed by lightheadedness (85%) and fatigue (81%). The vital signs of the patients showed an overall significant lowering of the heart rate during sitting (89.7 ± 17.9 versus 73.2 ± 12.1; p-value <0.05) and standing (100.5 ± 18.1 versus 80.9 ± 10.1; p-value <0.05) without a significant change in the blood pressure. Two patients had visual disturbances (luminous phenomena). Severe bradycardia and excessive flushing were seen in two patients, respectively. Another one patient reported joint pain and fatigue. CONCLUSION: This study indicates that 67% of children treated with ivabradine report an improvement in symptoms.

ROS/TRPA1/CGRP signaling mediates cortical spreading depression.

OBJECTIVES: The transient receptor potential ankyrin A 1 (TRPA1) channel and calcitonin gene-related peptide (CGRP) are targets for migraine prophylaxis. This study aimed to understand their mechanisms in migraine by investigating the role of TRPA1 in cortical spreading depression (CSD) in vivo and exploring how reactive oxygen species (ROS)/TRPA1/CGRP interplay in regulating cortical susceptibility to CSD. METHODS: Immunohistochemistry was used for detecting TRPA1 expression. CSD was induced by K+ on the cerebral cortex, monitored using electrophysiology in rats, and intrinsic optical imaging in mouse brain slices, respectively. Drugs were perfused into contralateral ventricle of rats. Lipid peroxidation (malondialdehyde, MDA) analysis was used for indicating ROS level. RESULTS: TRPA1 was expressed in cortical neurons and astrocytes of rats and mice. TRPA1 deactivation by an anti-TRPA1 antibody reduced cortical susceptibility to CSD in rats and decreased ipsilateral MDA level induced by CSD. In mouse brain slices, H2O2 facilitated submaximal CSD induction, which disappeared by the antioxidant, tempol and the TRPA1 antagonist, A-967079; Consistently, TRPA1 activation reversed prolonged CSD latency and reduced magnitude by the antioxidant. Further, blockade of CGRP prolonged CSD latency, which was reversed by H2O2 and the TRPA1 agonist, allyl-isothiocyanate, respectively. CONCLUSIONS: ROS/TRPA1/CGRP signaling plays a critical role in regulating cortical susceptibility to CSD. Inhibition ROS and deactivation of TRPA1 channels may have therapeutic benefits in preventing stress-triggered migraine via CGRP.

Role of implantable loop recorders in patients with postural orthostatic tachycardia syndrome.

INTRODUCTION: We previously reported on a subgroup of postural orthostatic tachycardia syndrome (POTS) patients who may also have features of neurocardiogenic syncope as well. In this subgroup of patients, we found syncope and presyncope were predominant clinical features. To understand the mechanism of syncope in this subgroup, we identified 39 patients who underwent loop recorder insertion. METHODS: We reviewed charts of 450 patients who had POTS and syncope seen at the University of Toledo Medical Center from 2003 to 2017. Thirty-nine patients had at least four episodes of syncope in the last 6 months and were included for this study. All of these patients had a prior evaluation with a Holter and an event monitor which were inconclusive. RESULTS: Thirty-nine patients, 33 (85%) women, aged 20-46 years, were included in this study. All patients demonstrated prolonged asystole (>6 seconds) or severe bradycardia (heart rate < 30 beats/min) during their syncope on implantable loop recorder (IRL). Fifteen patients demonstrated an asystole of >10 seconds and also had prolonged and convulsive syncope. All patients had abrupt syncope without any warning sign. All patients underwent dual-chamber pacemaker implantation using a closed loop stimulation algorithm. Syncope were completely eliminated in all patients following pacemaker implantation; however, they continued to have orthostatic tachycardia. CONCLUSION: POTS patients with unusually frequent syncope should be considered for ILR implantation if other monitoring modalities like 48-hour Holter monitor or event recorder are inconclusive. ILR may identify a subgroup of POTS patients who may benefit from pacemaker implantations.

Droxidopa in the Treatment of Postural Orthostatic Tachycardia Syndrome.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a constellation of signs and symptoms that occur when a patient is upright and relieved by recumbence. Currently, no drugs are labeled for the treatment for POTS. Droxidopa is an orally administered amino acid that is converted to norepinephrine and thought to improve both blood pressure and symptoms in patients with orthostatic intolerance. STUDY QUESTION: To appraise the effect of Droxidopa in a clinical setting in patients with POTS refractory to other forms of treatment. STUDY DESIGN: A retrospective study of patients with POTS at our Syncope and Autonomic Disorders Center. Three hundred fifty-two patients were screened, 54 of them were prescribed Droxidopa and found to be eligible to include in our study. MEASURES AND OUTCOME: Symptoms of orthostatic intolerance, side effects of therapy and response to treatment. Statistical analyses were done using SPSS software. Thirty-seven patients were included in data analysis. Patients who failed to follow up, didn't obtain Droxidopa due to insurance and cost concerns, had hypertensive response to therapy or had allergic reaction were excluded from data analysis. RESULTS: The most frequently reported symptom was dizziness in 91.9% of patients, followed by syncope and fatigue in 70.3% and 67.6% of patients, respectively. Symptoms of dizziness, syncope and fatigue were reported less after treatment; 75.7%, 51.4% and 40.5%, respectively. There was no statistically significant difference in standing or sitting blood pressure before and after treatment. Despite the improvement in some symptoms. Only 27% of patients reported improved quality of life after treatment. Of total, 40.5% of patients stopped the treatment either due to side effects or ineffectiveness. CONCLUSION: Droxidopa appears to improve some symptoms of orthostatic intolerance in patients with POTS but has diminutive impact on quality of life and blood pressure. Further assessment in large clinical trials is needed to evaluate its efficacy.

Role of closed loop stimulation pacing (CLS) in vasovagal syncope.

Vasovagal syncope (VVS) or neurocardiogenic syncope is defined by transient loss of consciousness with spontaneous and rapid recovery. Recently, a closed loop stimulation (CLS) pacing system has emerged as a new strategy which appears superior to conventional pacing for patients with refractory syncope. However, its efficacy remains of considerable debate and large randomized controlled clinical trials are needed. Between 2002 and 2017, 12 total studies evaluated the use of CLS pacing in patients with refractory VVS, and are summarized in this article.

Ivabradine in the treatment of postural tachycardia syndrome (POTS), a single center experience.

BACKGROUND: Ivabradine is a selective If  channel blocker that reduces heart rate without affecting other cardiovascular functions. In case reports and case series, it was shown to improve symptoms in patients with postural tachycardia syndrome (POTS). METHODOLOGY AND RESULTS: This retrospective study examined patients who were diagnosed with POTS and received ivabradine as part of their treatment. Forty-nine patients (47 females, 95.9%) received ivabradine. The average age was 35.1 ± 10.35 years. The most common symptoms were palpitations and lightheadedness and both improved significantly, 88.4% and 76.1% response rate, respectively. A total of 38 patients reported improvement in their symptoms. In addition, ivabradine resulted in an objective decrease in sitting and standing heart rate (78.1 ± 10.7 vs 72.5 ± 7.6, P-value: 0.01) and (107.4 ± 14.1 vs 95.1 ± 13.7, P-value: < 0.001), respectively, with no significant change in blood pressure. The most common reported side effect was luminous phenomena/visual brightness occurring in nine patients. However, none of the patients stopped ivabradine due to side effects. CONCLUSION: Our study shows that ivabradine is likely to be effective in treating patients with POTS. Nearly 78% of our cohort reported a significant improvement in symptoms with no major adverse effects reported. A future randomized, placebo-controlled trial is warranted.

The role of autoantibodies in the syndromes of orthostatic intolerance: a systematic review.

Orthostatic intolerance is defined as the provocation of symptoms upon standing, commonly caused by neurogenic orthostatic hypotension (OH) and postural tachycardia syndrome (POTS), the etiology for which has not been fully uncovered yet. Many reports have described the occurrence of dysautonomia, orthostatic intolerance and POTS following febrile illness, presumably viral and post-vaccine. Furthermore, patients with dysautonomia have higher rates of autoimmune disorders such as Hashimoto thyroiditis and SLE. Recent evidence has shown the presence of adrenergic and cholinergic receptor antibodies in patients with POTS and orthostatic hypotension. In patients with cholinergic receptor antibodies, higher titers correlate with the disease severity. Few reports have shown that immunomodulation therapy resulted in significant improvement in symptoms. In this article, we review the available literature correlating autoimmunity with orthostatic intolerance syndromes. Future studies are warranted to evaluate the prevalence of such antibodies and examine different treatment modalities in this sub group of patients.

Utility of High-Output His Pacing during Difficult AV Node Ablation. An Underutilized Strategy.

Atrioventricular (AV) node ablation is a commonly performed procedure for patients with chronic drug refractory atrial fibrillation (AF) with episodes of rapid ventricular response. We report on a 72-year-old man who had difficulty managing chronic drug refractory AFs with frequent hospitalizations for rapid ventricular rate. The patient was taken to the electrophysiology laboratory for AV node ablation. Extensive mapping and localization techniques of the compact AV node and ablation in the region were unsuccessful. Subsequently, high-output His bundle pacing using 20 mA at 2 ms of output energy was performed in an attempt to localize the His bundle in areas where high-output pacing resulted in a narrower QRS complex. Further ablations in the areas where pacing produced a narrower QRS complex resulted in complete heart block. This case highlights the importance of using this simple pacing maneuver to achieve complete heart block in patients in whom standard strategies to localize and ablate the compact AV node are unsuccessful.

Protection from noise-induced hearing loss by Kv2.2 potassium currents in the central medial olivocochlear system.

The central auditory brainstem provides an efferent projection known as the medial olivocochlear (MOC) system, which regulates the cochlear amplifier and mediates protection on exposure to loud sound. It arises from neurons of the ventral nucleus of the trapezoid body (VNTB), so control of neuronal excitability in this pathway has profound effects on hearing. The VNTB and the medial nucleus of the trapezoid body are the only sites of expression for the Kv2.2 voltage-gated potassium channel in the auditory brainstem, consistent with a specialized function of these channels. In the absence of unambiguous antagonists, we used recombinant and transgenic methods to examine how Kv2.2 contributes to MOC efferent function. Viral gene transfer of dominant-negative Kv2.2 in wild-type mice suppressed outward K(+) currents, increasing action potential (AP) half-width and reducing repetitive firing. Similarly, VNTB neurons from Kv2.2 knock-out mice (Kv2.2KO) also showed increased AP duration. Control experiments established that Kv2.2 was not expressed in the cochlea, so any changes in auditory function in the Kv2.2KO mouse must be of central origin. Further, in vivo recordings of auditory brainstem responses revealed that these Kv2.2KO mice were more susceptible to noise-induced hearing loss. We conclude that Kv2.2 regulates neuronal excitability in these brainstem nuclei by maintaining short APs and enhancing high-frequency firing. This safeguards efferent MOC firing during high-intensity sounds and is crucial in the mediation of protection after auditory overexposure.

Carbohydrate-restricted diet and acute coronary syndrome: a case report and review of this conflicting and yet unknown association.

We describe a case of a young patient, motivated to follow a carbohydrate-restricted diet intake for 6 years, who presented with an acute myocardial infarction.

Role of bradykinin and prostaglandin EP4 receptors in regulating TRPV1 channel sensitization in rat dorsal root ganglion neurons.

Transient receptor potential vanilloid type-1 (TRPV1) channels play key roles in chronic pain conditions and are modulated by different inflammatory mediators to elicit heat sensitisation. Bradykinin is a 9-amino acid peptide chain that promotes inflammation. The aim of present study is to investigate how bradykinin and prostaglandin receptors (EP3 and EP4 ) modulate the sensitisation of TRPV1-mediated responses. Calcium imaging studies of rat dorsal root ganglion (DRG) neurons were employed to investigate the desensitizing responses of TRPV1 ion channels by capsaicin, and the re-sensitization of TRPV1 by bradykinin, then to explore the role EP3 and EP4 receptors in mediating these bradykinin-dependent effects. Immunocytochemistry was used to study the co-expression and distribution of EP4, TRPV1, COX-1 and B2 in rat DRG neurons. Desensitization was seen upon repeated capsaicin application, we show that bradykinin-mediated sensitization of capsaicin-evoked calcium responses in rat DRG neurons occurs is dependent on COX-1 activity and utilizes a pathway that involves EP4 but not EP3 receptors. Immunocytochemical techniques revealed that EP4, TRPV1, COX-1 and B2 proteins are expressed mainly in small diameter (<1000 µm2 ) cell bodies of rat DRG neurons which are typically nociceptors. The present study provides suggestive evidence for a potential signalling pathway through which bradykinin may regulate TRPV1 ion channel function via EP4 receptors. In addition to confirming existing knowledge, the anatomical distribution and colocalization of these proteins in DRG neurons as revealed by this study offer valuable insight.

Autoimmunity in Syndromes of Orthostatic Intolerance: An Updated Review.

Orthostatic intolerance is a broad term that represents a spectrum of dysautonomic disorders, including postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH), as manifestations of severe autonomic failure. While the etiology of orthostatic intolerance has not yet fully been uncovered, it has been associated with multiple underlying pathological processes, including peripheral neuropathy, altered renin-aldosterone levels, hypovolemia, and autoimmune processes. Studies have implicated adrenergic, cholinergic, and angiotensin II type I autoantibodies in the pathogenesis of orthostatic intolerance. Several case series have demonstrated that immunomodulation therapy resulted in favorable outcomes, improving autonomic symptoms in POTS and OH. In this review, we highlight the contemporary literature detailing the association of autoimmunity with POTS and OH.

Impact of COVID-19 infection on baseline autonomic symptoms in patients with preexisting postural tachycardia syndrome and orthostatic intolerance: A retrospective study.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) and dysautonomia following a SARS-CoV-2 infection have been recently reported. The underlying mechanism of dysautonomia is not well understood. The impact of this viral illness on the underlying autonomic symptoms has not been studied in patients with a pre-existing POTS diagnosis. Our study aims to report the impact of a COVID-19 infection on patients with preexisting POTS, both during the acute phase of the disease and post-recovery. METHODS: Institutional Review Board (IRB) approval was obtained to access charts of the study subjects. All patients with known POTS disease who acquired COVID-19 infection between April 2020 and May 2021 were included. The end point of the study was worsening POTS related symptoms including orthostatic dizziness, palpitation, fatigue and syncope/ presyncope post COVID-19 infection that required escalation of therapy. Basic demographics, details of POTS diagnosis, medications, Additional information regarding COVID 19 infection, duration of illness, need for hospitalization, worsening of POTS symptoms, need for ED visits, the type of persisting symptoms and vaccination status were obtained from the retrospective chart review. RESULTS: A total of 41 patients were studied. The alpha-variant was the most common causing SARS-CoV-2 infection. 27% (11 patients) of them had tested positive for COVID- 19 infection more than once. About 38 (92.7%) of them reported having worsening of their baseline POTS symptoms during the active infection phase. About 28 patients (68%) experienced worsening of their dysautonomia symptoms for at least 1-6 months post infection. Nearly 30 patients (73.2%) required additional therapy for their symptom control and improvement. CONCLUSIONS: Patients with pre-existing POTS, most experienced a worsening of their baseline autonomic symptoms after suffering the COVID-19 infection which required additional pharmacotherapy for their symptom improvement.

The efficacy of non-pharmacological and non-pacing therapies in preventing vasovagal syncope: Tilt training, physical counter pressure maneuvers, and yoga - A systematic review and meta-analysis.

BACKGROUND: Vasovagal syncope (VVS) is a prevalent condition characterized by a sudden drop in blood pressure and heart rate, leading to a brief loss of consciousness and postural control. Recurrent episodes of VVS significantly impact the quality of life and are a common reason for emergency department visits. Non-pharmacological interventions, such as tilt training, physical counter pressure maneuvers, and yoga, have been proposed as potential treatments for VVS. However, their efficacy in preventing VVS remains uncertain. METHODS: A systematic review and meta-analysis were conducted following PRISMA guidelines. PubMed, Web of Science, and Embase were searched up to March 2023 for randomized controlled trials comparing non-pharmacological interventions with control in preventing VVS recurrence. The primary outcome was the recurrence rate of VVS episodes. RESULTS: A total of 1130 participants from 18 studies were included in the meta-analysis. The overall mean effect size for non-pharmacological interventions versus control was 0.245 (95 % CI: 0.128-0.471, p-value <0.001). Subgroup analysis showed that yoga had the largest effect size (odds ratio 0.068, 95 % CI: 0.018-0.250), while tilt training had the lowest effect size (odds ratio 0.402, 95 % CI: 0.171-0.946) compared to control. Physical counter pressure maneuvers demonstrated an odds ratio of 0.294 (95 % CI: 0.165-0.524) compared to control. CONCLUSION: Non-pharmacological interventions show promise in preventing recurrent VVS episodes. Yoga, physical counter pressure maneuvers, and tilt training can be considered as viable treatment options. Further research, including randomized studies comparing pharmacological and non-pharmacological approaches, is needed to evaluate the safety and efficacy of these interventions for VVS treatment.