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Introduction: Orthostatic intolerance is highly prevalent in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and is caused by an abnormal reduction in cerebral blood flow (CBF). In healthy controls (HCs), the regulation of CBF is complex and cardiac output (CO) is an important determinant of CBF: a review showed that a 30% reduction in CO results in a 10% reduction in CBF. In previous and separate ME/CFS studies, we showed that CO and CBF decreased to a similar extent during tilt testing., The Aim of the Study: to test the relationship between CBF and CO, which seems to be abnormal in ME/CFS patients and is different from that in HCs., Methods: In this retrospective study we analyzed this relationship in a large group of patients. To compare the patient data with those of HCs, we focused on patients with a normal heart rate (HR) and blood pressure (BP) response to upright tilt. Also, the influence of clinical data was analyzed. A total of 534 ME/CFS patients and 49 HCs underwent tilt testing with measurements of HR, BP, CBF, CO, and end-tidal PCO 2 . To measure CBF, extracranial Doppler flow velocity and vessel diameters were obtained using a GE echo system. The same device was used to measure suprasternal aortic flow velocities. End-tidal PCO 2 was recorded using a Nonin Lifesense device., Results: In 46 (9%) patients, CO and CBF changes were in the normal range for HCs, and in 488 (91%) an abnormal CO and CBF reduction was found. In patients with abnormal CO and CBF reductions, the slope of the regression line of CO versus CBF reduction was almost 1. The multiple regression analysis of the latter group showed that the CO reduction for the most part predicted the CBF reduction, with a limited role for the P ET CO 2 reduction., Conclusions: Two different patient groups with a normal HR and BP response during the tilt were identified: those with a CO and CBF in the normal range for HCs and those with an abnormal CO and CBF reduction during the tilt (91% of patients). In the latter group of patients, an almost 1:1 relationship between the CO and CBF reduction suggests the absence of compensatory vasodilation in the cerebral vasculature. This might indicate endothelial dysfunction in most ME/CFS patients and may have clinical and therapeutic implications.

Introduction : While the diagnosis of postural orthostatic tachycardia syndrome (POTS) is based on heart rate (HR) and blood pressure (BP) criteria, the pathophysiology of POTS is not fully understood as multiple pathophysiological mechanisms have been recognized. Also, cardiac function, being dependent on preload, afterload, contractility, and HR, has not been properly studied. Preload and contractility changes can be inferred from stroke volume index (SVI) changes during a tilt test. Afterload plays a minor role in POTS as a normal BP response is a prerequisite for POTS. Therefore, we analyzed the HR-SVI relation during a tilt test in myalgic encephalomyelitis (ME/CFS) patients with POTS and compared the data with ME/CFS patients with a normal HR-BP response and with that of healthy controls (HC). Material and Methods : In ME/CFS patients with either POTS ( n = 233) or a normal HR-BP response ( n = 507) and healthy controls ( n = 48), we measured SVI (by suprasternal echo), HR, and BP during the tilt. Results : In all ME/CFS patients, the decrease in SVI was larger compared to HC. In patients with a normal HR-BP response and in POTS patients with a HR increase between 30-39 bpm, there was an inverse relationship between the HR increase and SVI decrease during the tilt, compatible with increased venous pooling. In POTS patients with a HR increase ≥40 bpm, this inverse relation was lost, and SVI changes were significantly less compared to POTS patients with a HR increase between 30-39 bpm, suggestive of a hyperadrenergic response. Conclusions : In ME/CFS patients with POTS, two different hemodynamic profiles can be observed: in patients with a limited HR increase, mainly increased venous pooling is observed, while in patients with a large (≥ 40 bpm) HR increase the data are suggestive of a hyperadrenergic response. These two different profiles may have different therapeutic implications.

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To report the prevalence and severity of nonpelvic symptoms for patients with venous-origin chronic pelvic pain (VO-CPP) and to describe outcomes after pelvic vein stenting and embolization., Methods: We retrospectively reviewed outcomes of 45 women with VO-CPP who underwent treatment with iliac vein stenting and/or embolization. Patients completed symptom-severity questionnaires before and after treatment that assessed for pelvic pain, and multiple other symptoms, including brain fog, anxiety, depression, musculoskeletal pain, fatigue, migraines and more., Results: Patient age ranged from 18 to 65 years. The prevalence of common symptoms was as follows: migraines, 69%; brain fog, 76%; anxiety attacks, 58%; excess sweating, 64%; hip pain, 73%; diarrhea, 62%; constipation, 76%; and abdominal bloating, 82%. After treatment, most symptom scores improved by more than 50%; exceptions were excessive sweating (41% improvement) and bloating (47% improvement). Prevalence of individual symptoms that bundle into POTS ranged from 29% to 76%, where symptom improvement ranged from 23% to 59% after treatment. Overlapping individual symptoms characteristic of fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) were present in 64% to 82% of patients and all improved by 49% to 63% after treatment., Conclusions: Pelvic venous flow abnormality is linked causally to a spectrum of interrelated symptoms, of which many can be bundled into named syndromes of unknown cause. With catheter- based treatment of pelvic venous pooling, nonpelvic symptom and syndrome scores improved., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Despite there being a wide variety of symptoms reported in pediatric long COVID, one condition that has become increasingly recognized is orthostatic intolerance (OI), which can cause significant morbidity, limiting activities of daily living. This study examines rates of OI in 92 children with long COVID who underwent a bedside passive standing test in a pediatric post-COVID-19 rehabilitation clinic. Seventy-one percent met criteria for an orthostatic condition, including postural orthostatic tachycardia syndrome (POTS), orthostatic tachycardia (OT), classic orthostatic hypotension (OH), delayed OH, and orthostatic hypertension. Our findings suggest that OI is common in pediatric long COVID, necessitating appropriate clinical screening and treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This review discusses the varying definitions for post-acute sequelae of SARS CoV-2 infection (PASC) in adolescents and young adults (AYAs), symptom profiles of AYAs with PASC, and assessment and management strategies when AYAs present with symptoms concerning for PASC. Additionally, it reviews the impact that PASC can have on AYAs and includes strategies for providers to support AYAs with PASC. Finally, it concludes with a discussion around equity in the care of AYAs with possible PASC., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Comorbidities associated with venous origin chronic pelvic pain (VO-CPP) were evaluated pre and post venous treatment to assess change., Materials and Methods: 45 women with VO-CPP were treated with venous stenting and/or embolization. Four surveys assessed symptoms pre- and post-treatment: IPPS (chronic pelvic pain), PUF (interstitial cystitis), OHQ (dysautonomia), and modified ROME III (IBS). Prevalence of joint hypermobility was investigated., Results: Ages were 18-65. Pretreatment, 64% and 49% of women were in the severe range for PUF and OHQ, respectively. 40% and 56% met criteria for IBS and Ehlers-Danlos syndrome/Hypermobility Spectrum Disorder (EDS/HSD), respectively. 17eceived an iliac stent, 5 pelvic embolization, and 23 both. Post-treatment, average scores improved: IPPS (by 55%), PUF (34%), and OHQ (49%). Rome III improved only slightly., Conclusion: Pelvic pain, interstitial cystitis, and dysautonomia were frequently found with VO-CPP and improved after venous treatment. EDS/HSD and IBS were common in these women., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Dysautonomia, or dysfunction of the autonomic nervous system (ANS), may occur following an infectious insult and can result in a variety of debilitating, widespread, and often poorly recognized symptoms. Dysautonomia is now widely accepted as a complication of COVID-19 and is an important component of Post-Acute Sequelae of COVID-19 (PASC or long COVID). PASC shares many overlapping clinical features with other infection-associated chronic illnesses including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post-Treatment Lyme Disease Syndrome (PTLDS), suggesting that they may share common underlying mechanisms including autonomic dysfunction. Despite the recognition of this complication of Lyme disease in the care of patients with PTLD, there has been a scarcity of research in this field and dysautonomia has not yet been established as a complication of Lyme disease in the medical literature. In this review, we discuss the evidence implicating Borrelia burgdorferi as a cause of dysautonomia and the related symptoms, propose potential pathogenic mechanisms given our knowledge of Lyme disease and mechanisms of PASC and ME/CFS, and discuss the diagnostic evaluation and treatments of dysautonomia. We also outline gaps in the literature and priorities for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Adler, Chung, Rowe and Aucott.)

Purpose: Guanfacine is an α 2A -adrenergic receptor agonist, FDA-approved to treat attention-deficit hyperactivity disorder and high blood pressure, typically as an extended-release formulation up to 7 mg/day. In our dysautonomia clinic, we observed that off-label use of short-acting guanfacine at 1 mg/day facilitated symptom relief in two families with multiple members presenting with severe generalized anxiety. We also noted anecdotal improvements in associated dysautonomia symptoms such as hyperhidrosis, cognitive impairment, and palpitations. We postulated that a genetic deficit existed in these patients that might augment guanfacine susceptibility., Methods: We used whole-exome sequencing to identify mutations in patients with shared generalized anxiety and dysautonomia symptoms. Guanfacine-induced changes in the function of voltage-gated Na + channels were investigated using voltage-clamp electrophysiology., Results: Whole-exome sequencing uncovered the p.I739V mutation in SCN9A in the proband of two nonrelated families. Moreover, guanfacine inhibited ionic currents evoked by wild-type and mutant Na V 1.7 encoded by SCN9A, as well as other Na V channel subtypes to a varying degree., Conclusion: Our study provides further evidence for a possible pathophysiological role of Na V 1.7 in anxiety and dysautonomia. Combined with off-target effects on Na V channel function, daily administration of 1 mg short-acting guanfacine may be sufficient to normalize Na V channel mutation-induced changes in sympathetic activity, perhaps aided by partial inhibition of Na V 1.7 or other channel subtypes. In a broader context, expanding genetic and functional data about ion channel aberrations may enable the prospect of stratifying patients in which mutation-induced increased sympathetic tone normalization by guanfacine can support treatment strategies for anxiety and dysautonomia symptoms., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Craniocervical instability (CCI) is increasingly recognized in hereditary disorders of connective tissue and in some patients following suboccipital decompression for Chiari malformation (CMI) or low-lying cerebellar tonsils (LLCT). CCI is characterized by severe headache and neck pain, cervical medullary syndrome, lower cranial nerve deficits, myelopathy, and radiological metrics, for which occipital cervical fusion (OCF) has been advocated. We conducted a retrospective analysis of patients with CCI and Ehlers-Danlos syndrome (EDS) to determine whether the surgical outcomes supported the criteria by which patients were selected for OCF. Fifty-three consecutive subjects diagnosed with EDS, who presented with severe head and neck pain, lower cranial nerve deficits, cervical medullary syndrome, myelopathy, and radiologic findings of CCI, underwent open reduction, stabilization, and OCF. Thirty-two of these patients underwent suboccipital decompression for obstruction of cerebral spinal fluid flow. Questionnaire data and clinical findings were abstracted by a research nurse. Follow-up questionnaires were administered at 5-28 months (mean 15.1). The study group demonstrated significant improvement in headache and neck pain (p < 0.001), decreased use of pain medication (p < 0.0001), and improved Karnofsky Performance Status score (p < 0.001). Statistically significant improvement was also demonstrated for nausea, syncope (p < 0.001), speech difficulties, concentration, vertigo, dizziness, numbness, arm weakness, and fatigue (p = 0.001). The mental fatigue score and orthostatic grading score were improved (p < 0.01). There was no difference in pain improvement between patients with CMI/LLCT and those without. This outcomes analysis of patients with disabling CCI in the setting of EDS demonstrated significant benefits of OCF. The results support the reasonableness of the selection criteria for OCF. We advocate for a multi-center, prospective clinical trial of OCF in this population., (© 2023. The Author(s).)

Background and Objectives : During tilt testing, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience an abnormal reduction in cerebral blood flow (CBF). The relationship between this CBF reduction and symptom severity has not been examined in detail. Our hypothesis was that ME/CFS severity is related to the degree of the CBF reduction during tilt testing. Materials and Methods : First, from our database, we selected ME/CFS patients who had undergone assessments of ME/CFS symptomatology and tilt tests on the same day, one at the first visit and the second during a follow-up. The change in symptomatology was related to the change in CBF during the tilt test. Second, we combined the data of two previously published studies (n = 219), where disease severity as defined by the 2011 international consensus criteria (ICC) was available but not published. Results : 71 patients were retested because of worsening symptoms. The ICC disease severity distribution (mild-moderate-severe) changed from 51/45/4% at visit-1 to 1/72/27% at follow-up ( p < 0.0001). The %CBF reduction changed from initially 19% to 31% at follow-up ( p < 0.0001). Of 39 patients with stable disease, the severity distribution was similar at visit-1 (36/51/13%) and at follow-up (33/49/18%), p = ns. The %CBF reduction remained unchanged: both 24%, p = ns. The combined data of the two previously published studies showed that patients with mild, moderate, and severe disease had %CBF reductions of 25, 29, and 33%, respectively ( p < 0.0001). Conclusions : Disease severity and %CBF reduction during tilt testing are highly associated in ME/CFS: a more severe disease is related to a larger %CBF reduction. The data suggest a causal relationship where a larger CBF reduction leads to worsening symptoms.

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic, multi-system disorder that is characterized by a substantial impairment in the activities that were well tolerated before the illness. In an earlier report, we had described three adult women who met criteria for ME/CFS and orthostatic intolerance, and had congenital or acquired cervical spinal stenosis. All three experienced substantial global improvements in their ME/CFS and orthostatic intolerance symptoms after recognition and surgical treatment of the cervical stenosis. After a several year period of improvement, one of the individuals in that series experienced a return of ME/CFS and orthostatic intolerance symptoms., Main Symptoms and Clinical Findings: Radiologic investigation confirmed a recurrence of the ventral compression of the spinal cord due to a shift of the disc replacement implant at the involved cervical spinal level., Therapeutic Intervention: Decompression of the spinal cord with removal of the implant and fusion at the original C5-C6 level was once again followed by a similar degree of improvement in function as had been observed after the first operation., Conclusion: This recapitulation of the outcomes after surgical management of cervical stenosis provides further evidence in support of the hypothesis that cervical spinal stenosis can exacerbate pre-existing or cause new orthostatic intolerance and ME/CFS. Especially for those with refractory symptoms and neurological signs, surgical interventions may offer relief for selected patients with this complex condition., Competing Interests: SH was employed by Lifestrength Physical Therapy, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Edwards, Edwards, Heinlein and Rowe.)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating disease affecting millions of people worldwide. Due to the 2019 pandemic of coronavirus disease (COVID-19), we are facing a significant increase of ME/CFS prevalence. On May 11th to 12th, 2023, the second international ME/CFS conference of the Charité Fatigue Center was held in Berlin, Germany, focusing on pathomechanisms, diagnosis, and treatment. During the two-day conference, more than 100 researchers from various research fields met on-site and over 700 attendees participated online to discuss the state of the art and novel findings in this field. Key topics from the conference included: the role of the immune system, dysfunction of endothelial and autonomic nervous system, and viral reactivation. Furthermore, there were presentations on innovative diagnostic measures and assessments for this complex disease, cutting-edge treatment approaches, and clinical studies. Despite the increased public attention due to the COVID-19 pandemic, the subsequent rise of Long COVID-19 cases, and the rise of funding opportunities to unravel the pathomechanisms underlying ME/CFS, this severe disease remains highly underresearched. Future adequately funded research efforts are needed to further explore the disease etiology and to identify diagnostic markers and targeted therapies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Brain perfusion is sensitive to changes in CO 2 levels (CO 2 reactivity). Previously, we showed a pathological cerebral blood flow (CBF) reduction in the majority of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients during orthostatic stress. Limited data are available on the relation between CO 2 and CBF changes in ME/CFS patients. Therefore, we studied this relation between ME/CFS patients and healthy controls (HC) during tilt testing. In this retrospective study, supine and end-tilt CBF, as measured by extracranial Doppler flow, were compared with P ET CO 2 data in female patients either with a normal heart rate and blood pressure (HR/BP) response or with postural orthostatic tachycardia syndrome (POTS), and in HC. Five hundred thirty-five female ME/CFS patients and 34 HC were included. Both in supine position and at end-tilt, there was a significant relation between CBF and P ET CO 2 in patients (p < 0.0001), without differences between patients with a normal HR/BP response and with POTS. The relations between the %CBF change and the P ET CO 2 reduction were both significant in patients and HC (p < 0.0001 and p = 0.0012, respectively). In a multiple regression analysis, the patient/HC status and P ET CO 2 predicted CBF. The contribution of the P ET CO 2 to CBF changes was limited, with low adjusted R 2 values. In female ME/CFS patients, CO2 reactivity, as measured during orthostatic stress testing, is similar to that of HC and is independent of the type of hemodynamic abnormality. However, the influence of CO 2 changes on CBF changes is modest in female ME/CFS patients., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Introduction: During a standard 70-degree head-up tilt test, 90% of adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develop an abnormal reduction in cerebral blood flow (CBF). A 70-degree test might not be tolerated by young ME/CFS patients because of the high incidence of syncopal spells. This study examined whether a test at 20 degrees would be sufficient to provoke important reductions in CBF in young ME/CFS patients., Methods: We analyzed 83 studies of adolescent ME/CFS patients. We assessed CBF using extracranial Doppler measurements of the internal carotid and vertebral arteries supine and during the tilt. We studied 42 adolescents during a 20 degree and 41 during a 70 degree test., Results: At 20 degrees, no patients developed postural orthostatic tachycardia (POTS), compared to 32% at 70 degrees ( p  = 0.0002). The CBF reduction during the 20 degree tilt of -27(6)% was slightly less than during the reduction during a 70 degree test [-31(7)%; p  = 0.003]. Seventeen adolescents had CBF measurements at both 20 and 70 degrees. The CBF reduction in these patients with both a 20 and 70 degrees test was significantly larger at 70 degrees than at 20 degrees ( p  < 0.0001)., Conclusions: A 20 degree tilt in young ME/CFS patients resulted in a CBF reduction comparable to that in adult patients during a 70 degree test. The lower tilt angle provoked less POTS, emphasizing the importance of using the 70 degree angle for that diagnosis. Further study is needed to explore whether CBF measurements during tilt provide an improved standard for classifying orthostatic intolerance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor ZN declared a shared affiliation with the author PCR at the time of review., (© 2023 Van Campen, Rowe and Visser.)

Background: Orthostatic intolerance (OI) is a core diagnostic criterion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The majority of ME/CFS patients have no evidence of hypotension or postural orthostatic tachycardia syndrome (POTS) during head-up tilt, but do show a significantly larger reduction in stroke volume index (SVI) when upright compared to controls. Theoretically a reduction in SVI should be accompanied by a compensatory increase in heart rate (HR). When there is an incomplete compensatory increase in HR, this is considered chronotropic incompetence. This study explored the relationship between HR and SVI to determine whether chronotropic incompetence was present during tilt testing in ME/CFS patients., Methods: From a database of individuals who had undergone tilt testing with Doppler measurements for SVI both supine and end-tilt, we selected ME/CFS patients and healthy controls (HC) who had no evidence of POTS or hypotension during the test. To determine the relation between the HR increase and SVI decrease during the tilt test in patients, we calculated the 95% prediction intervals of this relation in HC. Chronotropic incompetence in patients was defined as a HR increase below the lower limit of the 95th % prediction interval of the HR increase in HC., Results: We compared 362 ME/CFS patients with 52 HC. At end-tilt, tilt lasting for 15 (4) min, ME/CFS patients had a significantly lower SVI (22 (4) vs. 27 (4) ml/m 2 ; p < 0.0001) and a higher HR (87 (11) vs. 78 (15) bpm; p < 0.0001) compared to HC. There was a similar relationship between HR and SVI between ME/CFS patients and HC in the supine position. During tilt ME/CFS patients had a lower HR for a given SVI; 37% had an inadequate HR increase. Chronotropic incompetence was more common in more severely affected ME/CFS patients., Conclusion: These novel findings represent the first description of orthostatic chronotropic incompetence during tilt testing in ME/CFS patients., (© 2023 Published by Elsevier Ltd on behalf of International Brain Research Organization.)

Persistent fatigue is one of the most common symptoms of post-COVID conditions, also termed long COVID. At the extreme end of the severity spectrum, some individuals with long COVID also meet the criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), raising the possibility that symptom management approaches for ME/CFS may benefit some long COVID patients. We describe the long-term outcomes of a 19-year-old male who developed profound impairment consistent with ME/CFS after a SARS-CoV-2 infection early in the pandemic. We evaluated and treated him using our clinic's approach to ME/CFS. This included a history and physical examination that ascertained joint hypermobility, pathological reflexes, physical therapy maneuvers to look for a range of motion restrictions in the limbs and spine, orthostatic testing, and screening laboratory studies. He was found to have profound postural tachycardia syndrome, several ranges of motion restrictions, and mast cell activation syndrome. He was treated according to our clinic's guidelines for managing ME/CFS, which included manual physical therapy maneuvers and both non-pharmacologic measures and medications directed at postural tachycardia syndrome and mast cell activation. He experienced significant improvement in his symptoms over 30 months. His case emphasizes how the application of the principles of treating ME/CFS has the potential to provide a direction for treating long COVID.

Individuals with Chiari malformation can present with symptoms of fatigue, lightheadedness, and syncope-the cardinal features of orthostatic intolerance. Similar orthostatic symptoms can complicate the clinical course following Chiari decompression. The presence of orthostatic intolerance in patients with Chiari malformation is not surprising given the location of the major circulatory control centers and their pathways in the brainstem. This article reviews the normal physiologic response to upright posture and the common forms of orthostatic intolerance encountered in clinical practice. The authors describe the relationship between orthostatic intolerance and Chiari malformation and provide suggestions regarding the evaluation and management of these disorders., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hypermobile Ehlers-Danlos syndrome (hEDS) is a common disorder in children and adolescents that negatively impacts health-related quality of life (HRQOL). It can include chronic pain, fatigue, autonomic dysfunction, and mood problems. The objective of this study was to examine levels of agreement between children and parents in the setting of hEDS and HRQOL. Individuals with hEDS, ages 10-20 years, and their parents were recruited to complete a series of surveys. Instruments included pediatric quality of life generic and multidimensional fatigue scales, Functional Disability Index, Pain-Frequency-Severity-Duration scale, Brief Illness Perception Questionnaire, and Herth Hope Index. Agreement on each measure was evaluated using statistical calculations. Thirty-six parent-child dyads completed the surveys. There were no significant differences between the means of parent and child scores. There was moderate to strong agreement on all survey scores. However, the proportion of dyads with disagreement was relatively high for each individual score. Eighteen dyads disagreed on at least half of the surveys. Body mass index centile and child perception of cognitive fatigue most strongly predicted disagreement in total HRQOL score. Proxy-reporters for children and adolescents with hEDS may agree with their child on average. However, due to significant frequency of clinically important disagreement, information from both children and their parents should be sought whenever possible.

Objectives: Patients with pelvic congestion syndrome (PCS) often report overlapping somatic symptoms and syndromes. The objective of this study was to explore the prevalence of co-existing symptoms and self-reported syndrome diagnoses among women with PCS and to inform future research hypotheses., Methods: A brief online survey was offered to members of a PCS support group website. Responses were assessed for self-reported co-existing symptoms and formal diagnoses, including: chronic fatigue syndrome, fibromyalgia, postural tachycardia syndrome, irritable bowel syndrome, migraines, interstitial cystitis, and temporomandibular joint dysfunction., Results: Of a total of 6000 members, there were 398 respondents; 232 (59%) had not yet been treated for PCS. Among these, the most prevalent co-existing symptoms were as follows: severe fatigue (72%), dizziness (63%), IBS symptoms (61%), brain fog (33%), migraines (49%), polyuria or dysuria (41%), excessive sweating (31%), TMJ pain (31%), and loose skin or lax joints (18%). These are much higher than reported for the general female population. The most commonly self-reported comorbid syndrome diagnoses for the overall group of 398 were: irritable bowel syndrome (29%), fibromyalgia (13%), spinal nerve problems (18%), interstitial cystitis (10%), postural tachycardia syndrome (9%), hypertension (11%), chronic fatigue syndrome (10%), and Ehlers-Danlos syndrome (6%). Other than with hypertension, these rates are variably higher than in the general population., Conclusion: Several self-reported co-existing symptoms and syndromes are more prevalent in members of a PCS support group relative to the reported prevalence in the general population. More formal investigation is warranted to evaluate this finding and to investigate potential etiologic links. Ehlers-Danlos Syndrome appears to be common in self identifying PCS women.

Background: Athletic underperformance is characterized by fatigue and an inability to sustain a consistent exercise workload. We describe five elite swimmers with prolonged fatigue and athletic underperformance. Based on our work in myalgic encephalomyelitis /chronic fatigue syndrome, we focused on orthostatic intolerance as a possible contributor to symptoms., Methods: Participants were referred for evaluation of fatigue and underperformance to the Chronic Fatigue Clinic at the Johns Hopkins Children's Center. All patients were evaluated for overtraining syndrome, as well as for features commonly seen in myalgic encephalomyelitis/chronic fatigue syndrome. The latter included joint hypermobility, orthostatic intolerance, and non-IgE mediated milk protein intolerance. Orthostatic intolerance was tested by performing a ten-minute passive standing test or a head-up tilt table test., Results: Orthostatic testing provoked fatigue and other symptoms in all five swimmers, two of whom met heart rate criteria for postural tachycardia syndrome. Treatment was individualized, primarily consisting of an increased intake of sodium chloride and fluids to address orthostasis. All patients experienced a relatively prompt improvement in fatigue and other orthostatic symptoms and were able to either return to their expected level of performance or improve their practice consistency., Conclusions: Orthostatic intolerance was an easily measured and treatable contributor to athletic underperformance in the five elite swimmers we describe. We suggest that passive standing tests or formal tilt table tests be incorporated into the clinical evaluation of athletes with fatigue and underperformance as well as into scientific studies of this topic. Recognition and treatment of orthostatic intolerance provides a new avenue for improving outcomes in underperforming athletes., (© 2022. The Author(s).)

Purpose of Review: To discuss emerging understandings of adolescent long COVID or post-COVID-19 conditions, including proposed clinical definitions, common symptoms, epidemiology, overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance, and preliminary guidance on management., Recent Findings: The recent World Health Organization clinical case definition of post-COVID-19 condition requires a history of probable or confirmed SARS-CoV-2 infection, with symptoms starting within 3 months of the onset of COVID-19. Symptoms must last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms of the post-COVID-19 condition include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction. These symptoms generally have an impact on everyday functioning. The incidence of prolonged symptoms following SARS-CoV-2 infection has proven challenging to define, but it is now clear that those with relatively mild initial infections, without severe initial respiratory disease or end-organ injury, can still develop chronic impairments, with symptoms that overlap with conditions like ME/CFS (profound fatigue, unrefreshing sleep, post-exertional malaise, cognitive dysfunction, and orthostatic intolerance)., Summary: We do not yet have a clear understanding of the mechanisms by which individuals develop post-COVID-19 conditions. There may be several distinct types of long COVID that require different treatments. At this point, there is no single pharmacologic agent to effectively treat all symptoms. Because some presentations of post-COVID-19 conditions mimic disorders such as ME/CFS, treatment guidelines for this and related conditions can be helpful for managing post-COVID-19 symptoms., Supplementary Information: The online version contains supplementary material available at 10.1007/s40124-022-00261-4., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.)

Objective: To examine demographic and clinical characteristics of individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with and without joint hypermobility We hypothesized that patients who were joint hypermobility-positive would have an earlier onset of ME/CFS symptoms as well as increased severity, a greater number of comorbid conditions, and a lower health-related quality of life., Study Design: From an observational cohort study of 55 individuals meeting the Fukuda criteria for ME/CFS, we compared groups using a Beighton score cutoff of 4 or higher to indicate joint hypermobility. Chart data were collected to examine the age and type of onset of ME/CFS and the presence of comorbid conditions. The impact on quality of life was assessed through questionnaires that included the Peds QL, Functional Disability Inventory, Peds QL Multidimensional Fatigue Scale, and Anxiety Subscale of the Symptom Checklist 90., Results: There was no significant difference between groups in mean ± SD age at onset of ME/CFS (13.3 ± 3.3 years vs 13.3 ± 2.3 years; P = .92), sex, frequency, and severity of ME/CFS symptoms, orthostatic intolerance symptoms, or comorbid conditions. There was no significant difference between the groups in measures of health-related quality of life using a Beighton score cutoff of 4 or a cutoff of 5 to define joint hypermobility., Conclusions: Despite being a risk factor for the development of ME/CFS, joint hypermobility as defined in this study was not associated with other clinical characteristics of the illness., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Objectives: Orthostatic intolerance (OI) is a clinical condition in which symptoms worsen upon assuming and maintaining upright posture and are ameliorated by recumbency. OI has a high prevalence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Limited data are available to guide the treatment of OI in ME/CFS patients. We and others have previously described patient-reported subjective improvement in symptoms using compression stockings. We hypothesized that these subjective reports would be accompanied by objective hemodynamic improvements. Materials and Methods: We performed a randomized crossover trial in 16 ME/CFS patients. Each underwent two 15-min head-up tilt table tests, one with and one without wearing knee-high compression stockings that provided 20-25 mm Hg compression. The order of the tests was randomized. We measured heart rate and blood pressure as well as cardiac output and cerebral blood flow (CBF) using extracranial Doppler of the internal carotid and vertebral arteries. Results : There were no differences in supine measurements between the 2 baseline measurements. There were no differences in heart rate and blood pressure at either end-tilt testing period. Compared to the test with the stockings off, the mean percentage reduction in cardiac output during the test with compression stockings on was lower, 15 (4)% versus 27 (6)% ( p < 0.0001), as was the mean percentage CBF reduction, 14 (4)% versus 25 (5)% ( p < 0.0001). Conclusion: In ME/CFS patients with orthostatic intolerance symptoms, cardiac output and CBF are significantly reduced during a tilt test. These abnormalities were present without demonstrable heart rate and blood pressure changes and were ameliorated by the use of compression stockings.

Background and Objectives : Symptoms and hemodynamic findings during orthostatic stress have been reported in both long-haul COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but little work has directly compared patients from these two groups. To investigate the overlap in these clinical phenotypes, we compared orthostatic symptoms in daily life and during head-up tilt, heart rate and blood pressure responses to tilt, and reductions in cerebral blood flow in response to orthostatic stress in long-haul COVID-19 patients, ME/CFS controls, and healthy controls. Materials and Methods : We compared 10 consecutive long-haul COVID-19 cases with 20 age- and gender-matched ME/CFS controls with postural tachycardia syndrome (POTS) during head-up tilt, 20 age- and gender-matched ME/CFS controls with a normal heart rate and blood pressure response to head-up tilt, and 10 age- and gender-matched healthy controls. Identical symptom questionnaires and tilt test procedures were used for all groups, including measurement of cerebral blood flow and cardiac index during the orthostatic stress. Results : There were no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood flow and cardiac index were more significantly reduced in the three patient groups compared with the healthy controls. Cardiac index reduction was not different between the three patient groups. The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the ME/CFS patients with a normal heart rate and blood pressure response. Conclusions : The symptoms of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1, SARS-CoV-2 infection acts as a trigger for the development of ME/CFS.

Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to enhance clinical care of POTS patients through research. This second (of two) articles summarizes current knowledge gaps, and outlines the clinical and research priorities for POTS. POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance and orthostatic tachycardia without hypotension. Patients often experience a host of other related disabling symptoms. The functional and economic impacts of this disorder are significant. The pathophysiology remains incompletely understood. Beyond the significant gaps in understanding the disorder itself, there is a paucity of evidence to guide treatment which can contribute to suboptimal care for this patient population. The vast majority of physicians have minimal to no familiarity or training in the assessment and management of POTS. Funding for POTS research remains very low relative to the size of the patient population and impact of the syndrome. In addition to efforts to improve awareness and physician education, an investment in research infrastructure including the development of standardized disease-specific evaluation tools and outcome measures is needed to facilitate effective collaborative research. A national POTS research consortium could facilitate well-controlled multidisciplinary clinical research studies and therapeutic trials. These priorities will require a substantial increase in the number of research investigators and the amount of research funding in this area., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Orthostatic symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may be caused by an abnormal reduction in cerebral blood flow. An abnormal cerebral blood flow reduction was shown in previous studies, without information on the recovery pace of cerebral blood flow. This study examined the prevalence and risk factors for delayed recovery of cerebral blood flow in ME/CFS patients., Methods: 60 ME/CFS adults were studied: 30 patients had a normal heart rate and blood pressure response during the tilt test, 4 developed delayed orthostatic hypotension, and 26 developed postural orthostatic tachycardia syndrome (POTS) during the tilt. Cerebral blood flow measurements, using extracranial Doppler, were made in the supine position pre-tilt, at end-tilt, and in the supine position at 5 min post-tilt. Also, cardiac index measurements were performed, using suprasternal Doppler imaging, as well as end-tidal PCO2 measurements. The change in cerebral blood flow from supine to end-tilt was expressed as a percent reduction with mean and (SD). Disease severity was scored as mild (approximately 50% reduction in activity), moderate (mostly housebound), or severe (mostly bedbound)., Results: End-tilt cerebral blood flow reduction was -29 (6)%, improving to -16 (7)% at post-tilt. No differences in either end-tilt or post-tilt measurements were found when patients with a normal heart rate and blood pressure were compared to those with POTS, or between patients with normocapnia (end-tidal PCO2 ≥ 30 mmHg) versus hypocapnia (end-tidal PCO2 < 30 mmHg) at end-tilt. A significant difference was found in the degree of abnormal cerebral blood flow reduction in the supine post-test in mild, moderate, and severe ME/CFS: mild: cerebral blood flow: -7 (2)%, moderate: -16 (3)%, and severe :-25 (4)% (p all < 0.0001). Cardiac index declined significantly during the tilt test in all 3 severity groups, with no significant differences between the groups. In the supine post-test cardiac index returned to normal in all patients., Conclusions: During tilt testing, extracranial Doppler measurements show that cerebral blood flow is reduced in ME/CFS patients and recovery to normal supine values is incomplete, despite cardiac index returning to pre-tilt values. The delayed recovery of cerebral blood flow was independent of the hemodynamic findings of the tilt test (normal heart rate and blood pressure response, POTS, or delayed orthostatic hypotension), or the presence/absence of hypocapnia, and was only related to clinical ME/CFS severity grading. We observed a significantly slower recovery in cerebral blood flow in the most severely ill ME/CFS patients., Significance: The finding that orthostatic stress elicits a post-stress cerebral blood flow reduction and that disease severity greatly influences the cerebral blood flow reduction may have implications on the advice of energy management after a stressor and on the advice of lying down after a stressor in these ME/CFS patients., (© 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Atlanto-axial instability (AAI) is common in the connective tissue disorders, such as rheumatoid arthritis, and increasingly recognized in the heritable disorders of Stickler, Loeys-Dietz, Marfan, Morquio, and Ehlers-Danlos (EDS) syndromes, where it typically presents as a rotary subluxation due to incompetence of the alar ligament. This retrospective, IRB-approved study examines 20 subjects with Fielding type 1 rotary subluxation, characterized by anterior subluxation of the facet on one side, with a normal atlanto-dental interval. Subjects diagnosed with a heritable connective tissue disorder, and AAI had failed non-operative treatment and presented with severe headache, neck pain, and characteristic neurological findings. Subjects underwent a modified Goel-Harms posterior C1-C2 screw fixation and fusion without complication. At 15 months, two subjects underwent reoperation following a fall (one) and occipito-atlantal instability (one). Patients reported improvement in the frequency or severity of neck pain (P < 0.001), numbness in the hands and lower extremities (P = 0.001), headaches, pre-syncope, and lightheadedness (all P < 0.01), vertigo and arm weakness (both P = 0.01), and syncope, nausea, joint pain, and exercise tolerance (all P < 0.05). The diagnosis of Fielding type 1 AAI requires directed investigation with dynamic imaging. Alignment and stabilization is associated with improvement of pain, syncopal and near-syncopal episodes, sensorimotor function, and exercise tolerance.

Background: Orthostatic intolerance (OI) is a frequent finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Published studies have proposed that deconditioning is an important pathophysiological mechanism in various forms of OI, including postural orthostatic tachycardia syndrome (POTS), however conflicting opinions exist. Deconditioning can be classified objectively using the predicted peak oxygen consumption (VO 2 ) values from cardiopulmonary exercise testing (CPET). Therefore, if deconditioning is an important contributor to OI symptomatology, one would expect a relation between the degree of reduction in peak VO 2 during CPET and the degree of reduction in CBF during head-up tilt testing (HUT)., Methods and Results: In 22 healthy controls and 199 ME/CFS patients were included. Deconditioning was classified by the CPET response as follows: %peak VO 2  ≥ 85% = no deconditioning, %peak VO 2 65-85% = mild deconditioning, and %peak VO 2  < 65% = severe deconditioning. HC had higher oxygen consumption at the ventilatory threshold and at peak exercise as compared to ME/CFS patients (p ranging between 0.001 and < 0.0001). Although ME/CFS patients had significantly greater CBF reduction than HC (p < 0.0001), there were no differences in CBF reduction among ME/CFS patients with no, mild, or severe deconditioning. We classified the hemodynamic response to HUT into three categories: those with a normal heart rate and blood pressure response, postural orthostatic tachycardia syndrome, or orthostatic hypotension. No difference in the degree of CBF reduction was shown in those three groups., Conclusion: This study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO 2 results on cardiopulmonary exercise testing.

Background: The proclivity to atlantoaxial instability (AAI) has been widely reported for conditions such as rheumatoid arthritis and Down syndrome. Similarly, we have found a higher than expected incidence of AAI in hereditary connective tissue disorders. We demonstrate a strong association of AAI with manifestations of dysautonomia, in particular syncope and lightheadedness, and make preliminary observations as to the salutary effect of surgical stabilization of the atlantoaxial motion segment., Methods: In an institutional review board-approved retrospective study, 20 subjects (16 women, 4 men) with hereditary connective tissue disorders had AAI diagnosed by computed tomography. Subjects underwent realignment (reduction), stabilization, and fusion of the C1-C2 motion segment. All subjects completed preoperative and postoperative questionnaires in which they were asked about performance, function, and autonomic symptoms, including lightheadedness, presyncope, and syncope., Results: All patients with AAI reported lightheadedness, and 15 had refractory syncope or presyncope despite maximal medical management and physical therapy. Postoperatively, subjects reported a statistically significant improvement in lightheadedness (P = 0.003), presyncope (P = 0.006), and syncope (P = 0.03), and in the frequency (P < 0.05) of other symptoms related to autonomic function, such as nausea, exercise intolerance, palpitations, tremors, heat intolerance, gastroesophageal reflux, and sleep apnea., Conclusions: This study draws attention to the potential for AAI to present with syncope or presyncope that is refractory to medical management, and for surgical stabilization of AAI to lead to improvement of these and other autonomic symptoms., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Muscle pain and fibromyalgia (FM) are common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We recently demonstrated that during orthostatic stress testing, adults with ME/CFS reported increased pain. In the current study, we hypothesised that pain pressure thresholds (PPT) would decrease and temporal summation (windup) would increase after head-up tilt testing (HUT), and that the presence of co-morbid FM would be associated with greater change in both measures., Methods: We studied adult ME/CFS patients undergoing HUT. PPT and temporal summation (or windup) measurements were obtained pre- and post-HUT at the finger and shoulder., Results: 248 ME/CFS patients (164 with FM and 84 without FM), and 22 healthy controls (HC) were analysed. In HC there were no significant differences in PPT between pre- and post- HUT (finger: from 4.7(1.6) to 4.4(1.5); shoulder: from 2.8(1.0) to 2.9(1.0)). In ME/CFS patients with and without FM, a significant decrease in PPT post-HUT was found compared to HC (both p<0.0001). Patients with FM had a lower PPT pre- and post-HUT (finger: from 2.0(0.9) to 1.5(0.8); shoulder: from 1.2(0.5) to 1.0(0.5) compared to patients without FM (finger: from 5.0(1.6) to 3.3(1.5); shoulder: from 2.2(0.9) to1.9(1.0) (p ranging from 0.001 to <0.0001). Windup in HC did not significantly change from pre- to post-HUT. In ME/CFS patients with and without FM windup was increased compared to HC pre-HUT (both p<0.0001), but did not significantly change post-HUT., Conclusions: Pressure pain threshold decreased in ME/CFS patients with or without fibromyalgia after head-up tilt test (HUT), but did not change post-HUT in healthy controls. Windup pre- and post-HUT was significantly higher compared to healthy controls, but did not change from pre- to post-HUT. These results demonstrate that, like exercise, orthostatic stress can negatively influence the physiology of pain perception in ME/CFS. Furthermore, the physiology of pain perception is even more negatively influenced by concomitant fibromyalgia.

Introduction: Fatigue is a common acute symptom following SARS-CoV-2 infection (COVID-19). The presence of persistent fatigue and impaired daily physical and cognitive function has led to speculation that like SARS-CoV-1 infection, COVID-19 will be followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Methods and Results: We describe three adolescent and young adult patients who had confirmed or probable COVID-19 infections early on during the pandemic and were referred for evaluation to the Chronic Fatigue Clinic at the Johns Hopkins Children's Center. All patients reported orthostatic intolerance symptoms within the first 2 weeks of illness, and 10-min passive standing tests were consistent with postural tachycardia syndrome. After 6 months of illness, all three patients met criteria for ME/CFS. Clinical features of interest included strong histories of allergies in all three patients, two of whom had elevations in plasma histamine. Each demonstrated limitations in symptom-free range of motion of the limbs and spine and two presented with pathological Hoffman reflexes. These comorbid features have been reported in adolescents and young adults with ME/CFS. Conclusion: ME/CFS can be triggered by COVID-19 in adolescents and young adults. Further work is needed to determine the pathogenesis of ME/CFS after COVID-19 and optimal methods of treating these patients. Our preliminary study calls attention to several comorbid features that deserve further attention as potential targets for intervention. These include neuromuscular limitations that could be treated with manual forms of therapy, orthostatic intolerance and POTS for which there are multiple medications and non-pharmacologic therapies, treatable allergic and mast cell phenomena, and neurologic abnormalities that may require specific treatment. Larger studies will need to ascertain the prevalence of these abnormalities., Competing Interests: RLV was employed by company Rick Violand, PT, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Petracek, Suskauer, Vickers, Patel, Violand, Swope and Rowe.)

Introduction: Muscle pain, fatigue, and concentration problems are common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These symptoms are commonly increased as part of the phenomenon of postexertional malaise (PEM). An increase in the severity of these symptoms is described following physical or mental exercise in ME/CFS patients. Another important symptom of ME/CFS is orthostatic intolerance, which can be detected by head-up tilt testing (HUT). The effect of HUT on PEM has not been studied extensively. For this purpose, we assessed numeric rating scales (NRS) for pain, fatigue, and concentration pre- and post-HUT. As pain is a core symptom in fibromyalgia (FM), we subgrouped ME/CFS patients by the presence or absence of FM. Methods and Results: In eligible ME/CFS patients who underwent HUT, NRS of pain, fatigue, and concentration were obtained pre-HUT, immediately after HUT, at 24 and 48 h, and at 7 days posttest. We studied 174 ME/CFS patients with FM, 104 without FM, and 30 healthy controls (HC). Values for all symptoms were unchanged for HC pre- and post-HUT. Compared with pre-HUT, the three NRS post-HUT were significantly elevated in both ME/CFS patient groups even after 7 days. NRS pain was significantly higher at all time points measured in the ME/CFS patients with FM compared with those without FM. In ME/CFS patients, the maximum fatigue and concentration scores occurred directly post-HUT, whereas pain perception reached the maximum 24 h post-HUT. Conclusion: NRS scores of pain, fatigue, and concentration were significantly increased even at 7 days post-HUT compared with pre-HUT in ME/CFS patients with and without FM, suggesting that orthostatic stress is an important determinant of PEM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van Campen, Rowe, Verheugt and Visser.)

Background: Finger plethysmography derived stroke volumes are frequently measured during tilt table testing. There are two algorithms to determine stroke volumes: Modelflow and Nexfin CO Trek. Most tilt studies used Modelflow, while there are differences between the two algorithms., Objective: To compare stroke volume indices by Nexfin CO Trek (SVINexfinCOTrek) with suprasternal Doppler derived SVI (SVIDoppler) in healthy controls (HC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients during tilt testing. These patients may have a large SVI decrease during the tilt enabling a large range of SVI to be studied., Methods: One hundred and fifty-four patients and 39 HC with a normal tilt test were included. Supine and end-tilt SVIDoppler and SVINexfinCOTrek were compared using the Bland-Altman analysis. Also, the effect of calibrating supine SVINexfinCOTrek to SVIDoppler was studied., Results: Supine and end-tilt SVINexfinCOTrek were significantly higher than SVIDoppler: both P< 0.005. Bias, limits of agreement, and percent error (PE) were high with PE's between 37 and 43%. The calibration procedure resulted in an acceptable variance with a PE of 29%., Conclusions: SVINexfinCOTrek overestimates stroke volumes compared to SVIDoppler, leading to high PE's. Calibration reduced variance to an acceptable level, allowing SVINexfinCOTrek to be used for assessment of SVI changes during tilt testing.

Introduction: In a large study with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients, we showed that 86% had symptoms of orthostatic intolerance in daily life and that 90% had an abnormal reduction in cerebral blood flow (CBF) during a standard tilt test. A standard head-up tilt test might not be tolerated by the most severely affected bed-ridden ME/CFS patients. Sitting upright is a milder orthostatic stress. The present study examined whether a sitting test, measuring cerebral blood flow by extracranial Doppler, would be sufficient to provoke abnormal reductions in cerebral blood flow in severe ME/CFS patients., Methods and Results: 100 severe ME/CFS patients were studied, (88 females) and were compared with 15 healthy controls (HC) (13 females). CBF was measured first while seated for at least one hour, followed by a CBF measurement in the supine position. Fibromyalgia was present in 37 patients. Demographic data as well as supine heart rate and blood pressures were not different between ME/CFS patients and HC. Heart rate and blood pressure did not change significantly between supine and sitting both in patients and HC. Supine CBF was not different between patients and HC. In contrast, absolute CBF during sitting was lower in patients compared to HC: 474 (96) mL/min in patients and 627 (89) mL/min in HC; p < 0.0001. As a result, percent CBF reduction while seated was -24.5 (9.4)% in severe ME/CFS patients and -0.4 (1.2)% in HC ( p < 0.0001). In the ten patients who had no orthostatic intolerance complaints in daily life, the CBF reduction was -2.7 (2.1)%, which was not significantly different from HC ( p = 0.58). The remaining 90 patients with orthostatic intolerance complaints had a -26.9 (6.2)% CBF reduction. No difference in CBF parameters was found in patients with and without fibromyalgia. Patients with a previous diagnosis of postural orthostatic tachycardia syndrome (POTS) had a significantly larger CBF reduction compared with those without POTS: 28.8 (7.2)% vs. 22.3 (9.7)% ( p = 0.0008)., Conclusions: A sitting test in severe ME/CFS patients was sufficient to provoke a clinically and statistically significant mean CBF decline of 24.5%. Patients with a previous diagnosis of POTS had a larger CBF reduction while seated, compared to patients without POTS. The magnitude of these CBF reductions is similar to the results in less severely affected ME/CFS patients during head-up tilt, suggesting that a sitting test is adequate for the diagnosis of orthostatic intolerance in severely affected patients.

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe and disabling chronic disease. Grading patient's symptom and disease severity for comparison and therapeutic decision-making is necessary. Clinical grading that depends on patient self-report is subject to inter-individual variability. Having more objective measures to grade and confirm clinical grading would be desirable. Therefore, the aim of this study was to validate the clinical severity grading that has been proposed by the authors of the ME International Consensus Criteria (ICC) using more standardized measures like questionnaires, and objective measures such as physical activity tracking and cardiopulmonary exercise testing., Methods and Results: The clinical database of a subspecialty ME/CFS clinic was searched for patients who had completed the SF 36 questionnaire, worn a Sensewear TM armband for five days, and undergone a cardiopulmonary exercise test. Only patients who completed all three investigations within 3 months from each other-to improve the likelihood of stable disease-were included in the analysis. Two-hundred-eighty-nine patients were analyzed: 121 were graded as mild, 98 as moderate and 70 as having severe disease. The mean (SD) physical activity subscale of the SF-36 was 70 (11) for mild, 43 (8) for moderate and 15 (10) for severe ME/CFS patients. The mean (SD) number of steps per day was 8235 (1004) for mild, 5195 (1231) for moderate and 2031 (824) for severe disease. The mean (SD) percent predicted oxygen consumption at the ventilatory threshold was 47 (11)% for mild, 38 (7)% for moderate and 30 (7)% for severe disease. The percent peak oxygen consumption was 90 (14)% for mild, 64 (8)% for moderate and 48 (9)% for severe disease. All comparisons were p < 0.0001., Conclusion: This study confirms the validity of the ICC severity grading. Grading assigned by clinicians on the basis of patient self-report created groups that differed significantly on measures of activity using the SF-36 physical function subscale and objective measures of steps per day and exercise capacity. There was variability in function within severity grading groups, so grading based on self-report can be strengthened by the use of these supplementary measures.

Introduction: Effort intolerance along with a prolonged recovery from exercise and post-exertional exacerbation of symptoms are characteristic features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The gold standard to measure the degree of physical activity intolerance is cardiopulmonary exercise testing (CPET). Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, and that a 2-day CPET protocol further discriminates between ME/CFS patients and sedentary controls. Limited information is present on ME/CFS patients with a severe form of the disease. Therefore, the aim of this study was to compare the effects of a 2-day CPET protocol in female ME/CFS patients with a severe grade of the disease to mildly and moderately affected ME/CFS patients., Methods and Results: We studied 82 female patients who had undergone a 2-day CPET protocol. Measures of oxygen consumption (VO 2 ), heart rate (HR) and workload both at peak exercise and at the ventilatory threshold (VT) were collected. ME/CFS disease severity was graded according to the International Consensus Criteria. Thirty-one patients were clinically graded as having mild disease, 31 with moderate and 20 with severe disease. Baseline characteristics did not differ between the 3 groups. Within each severity group, all analyzed CPET parameters (peak VO 2 , VO 2 at VT, peak workload and the workload at VT) decreased significantly from day-1 to day-2 ( p -Value between 0.003 and <0.0001). The magnitude of the change in CPET parameters from day-1 to day-2 was similar between mild, moderate, and severe groups, except for the difference in peak workload between mild and severe patients ( p = 0.019). The peak workload decreases from day-1 to day-2 was largest in the severe ME/CFS group (-19 (11) %)., Conclusion: This relatively large 2-day CPET protocol study confirms previous findings of the reduction of various exercise variables in ME/CFS patients on day-2 testing. This is the first study to demonstrate that disease severity negatively influences exercise capacity in female ME/CFS patients. Finally, this study shows that the deterioration in peak workload from day-1 to day-2 is largest in the severe ME/CFS patient group.

Introduction: Orthostatic intolerance (OI) is common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Cognitive dysfunction has been demonstrated during head-up tilt testing (HUT) in those with ME/CFS: worse scores on cognitive tests occur with increasing tilt angles and increasing complexity of the cognitive challenge. The aim of our study was to determine whether cognitive impairment persists after completion of HUT., Methods and Results: Eligible participants were consecutive individuals satisfying criteria for ME/CFS who underwent HUT because of OI. The 2- and 3-back tests were performed before the start of HUT and within 5 min after completion of HUT. We measured the percentage of correct responses and raw reaction times before and after HUT for both the 2- and 3-back tests. We studied 128 ME/CFS patients who underwent HUT and had a complete set of N-back data before and after HUT. Compared to pre-tilt responses, the percentage of correct responses on the 2-back test decreased post-HUT from 77(18) to 62(21) and of the 3-back test from 57(17) to 41(17) (both p < 0.0001). The raw reaction time of the 2-back test increased post-HUT from 783(190) to 941(234) m/s and of the 3-back test from 950(170) to 1102(176) (both p < 0.0001). There was no difference in the N-back test data for subgroups dichotomized based on disease severity, the presence of co-morbid fibromyalgia, or the presence of postural orthostatic tachycardia syndrome., Conclusion: As measured by the N-back test, working memory remains impaired in adults with ME/CFS following a 30-min head-up tilt test., (Copyright © 2020 van Campen, Rowe, Verheugt and Visser.)

Introduction: In a study of 429 adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we demonstrated that 86% had symptoms of orthostatic intolerance in daily life. Using extracranial Doppler measurements of the internal carotid and vertebral arteries during a 30-min head-up tilt to 70 degrees, 90% had an abnormal reduction in cerebral blood flow (CBF). A standard head-up tilt test of this duration might not be tolerated by the most severely affected bed-ridden ME/CFS patients. This study examined whether a shorter 15-min test at a lower 20 degree tilt angle would be sufficient to provoke reductions in cerebral blood flow in severe ME/CFS patients., Methods and Results: Nineteen severe ME/CFS patients with orthostatic intolerance complaints in daily life were studied: 18 females. The mean (SD) age was 35(14) years, body surface area (BSA) was 1.8(0.2) m 2 and BMI was 24.0(5.4) kg/m 2 . The median disease duration was 14 (IQR 5-18) years. Heart rate increased, and stroke volume index and end-tidal CO 2 decreased significantly during the test ( p ranging from <0.001 to <0.0001). The cardiac index decreased by 26(7)%: p < 0.0001. CBF decreased from 617(72) to 452(63) mL/min, a 27(5)% decline. All 19 severely affected ME/CFS patients met the criteria for an abnormal CBF reduction., Conclusions: Using a less demanding 20 degree tilt test for 15 min in severe ME/CFS patients resulted in a mean CBF decline of 27%. This is comparable to the mean 26% decline previously noted in less severely affected patients studied during a 30-min 70 degree head-up tilt. These observations have implications for the evaluation and treatment of severely affected individuals with ME/CFS.

Background: Most studies to assess effort intolerance in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have used questionnaires. Few studies have compared questionnaires with objective measures like an actometer or an exercise test. This study compared three measures of physical activity in ME/CFS patients: the physical functioning scale (PFS) of the SF-36, the number of steps/day (Steps) using an actometer, and the %peak VO 2 of a cardiopulmonary stress test., Methods: Female ME/CFS patients were selected from a clinical database if the three types of measurements were available, and the interval between measurements was ≤ 3 months. Data from the three measures were compared by linear regression., Results: In 99 female patients the three different measures were linearly, significantly, and positively correlated (PFS vs Steps, PFS vs %peak VO 2 and Steps vs %peak VO 2 : all P < 0.001). Subgroup analysis showed that the relations between the three measures were not different in patients with versus without fibromyalgia and with versus without a maximal exercise effort (RER ≥ 1.1). In 20 patients re-evaluated for symptom worsening, the mean of all three measures was significantly lower (P < 0.0001), strengthening the observation of the relations between them. Despite the close correlation, we observed a large variation between the three measures in individual patients., Conclusions: Given the large variation in ME/CFS patients, the use of only one type of measurement is inadequate. Integrating the three modalities may be useful for patient care by detecting overt discrepancies in activity and may inform studies that compare methods of improving exercise capacity.

The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of "mast cell activation syndrome" (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a "consensus" (re-termed here as "consensus-1"). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as "consensus-2"), resembling "consensus-1" in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by "consensus-2" criteria has potential to be problematic, but underdiagnosis by "consensus-1" criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful., (©2020 Lawrence B. Afrin et al., published by De Gruyter, Berlin/Boston.)

Objective: The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI., Methods: 429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms., Results: End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P < .0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P < .0005)., Conclusions: During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities., Significance: This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients., (© 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Following concussion, children often experience nonspecific symptoms that overlap with those of other common pediatric conditions, including orthostatic intolerance (OI). The primary goal of this study was to evaluate OI in youth presenting for clinical care for concussion and reporting symptoms frequently observed in OI. Eighty-two of 114 patients aged 10 to 22 years endorsed symptoms based on 8 screening questions, and 24 of those 82 patients met criteria for OI based on an active standing test. No screening question generated clinically useful likelihood ratios for predicting OI. The prevalence of OI in this cohort is considerably higher than estimates in the general pediatric population, suggesting a link between concussion and OI. Future work is needed to evaluate the best method of testing for OI, the natural history of OI symptoms in youth with concussion, and the response to intervention in children with both concussion and OI.