Phenylephrine alters phase synchronization between cerebral blood velocity and blood pressure in ME/CFS with orthostatic intolerance.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neurocognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between arterial pressure (AP) and cerebral blood velocity (CBV) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age = 24.1 yr) and 15 patients with ME/CFS (mean age = 21.8 yr). All patients with ME/CFS had postural tachycardia syndrome (POTS). A 10-min 60° head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decreased end-tidal CO2 (ETCO2; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, P < 0.05) in ME/CFS versus control. In ME/CFS, HUT significantly decreased CBV compared with control (-22.5% vs. -8.7%, P < 0.005). To mitigate the orthostatic CBV reduction, we administered supplemental CO2, phenylephrine, and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n = 4 N-back during HUT in ME/CFS similar to control (ME/CFS = 38.5 ± 5.5 vs. ME/CFS + PE= 65.6 ± 5.7 vs. Control 56.9 ± 7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. Although CO2 and acetazolamide had no effect on PhSI in ME/CFS, phenylephrine caused a significant reduction in PhSI (ME/CFS = 0.80 ± 0.03 vs. ME/CFS + PE= 0.69 ± 0.04, P < 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in patients with ME/CFS, perhaps related to improved neurovascular coupling, cerebral autoregulation, and maintenance of CBV.NEW & NOTEWORTHY We evaluated cognitive function before and after CO2, acetazolamide, and phenylephrine, which mitigate orthostatic reductions in cerebral blood velocity. Neither CO2 nor acetazolamide affected N-back testing (% correct answers) during an orthostatic challenge. Only phenylephrine improved upright N-back performance in ME/CFS, as it both blocked hyperventilation and increased CO2 significantly compared with those untreated. And only phenylephrine resulted in improved PSI values in both ME/CFS and control while upright, suggesting improved cerebral autoregulation.

Small fiber neuropathy in children, adolescents, and young adults with chronic orthostatic intolerance and postural orthostatic tachycardia syndrome: A retrospective study.

PURPOSE: To determine in children, adolescent and young adult (CAYA) patients presenting with Orthostatic Intolerance (OI) or Postural Orthostatic Tachycardia Syndrome (POTS) associated with the additional symptoms of neuropathic discomfort (pain, paresthesia and/or allodynia): 1) the incidence of small fiber neuropathy, and 2) assess if there was serologic evidence for an underlying inflammatory or autoimmune state. METHODS: A cohort of 109 CAYA patients with the above symptoms underwent epidermal skin biopsy for nerve fiber density. Blood biomarkers for inflammation were tested (CRP, ESR, ANA, complement (C3), thyroid function testing with antibodies (thyroid peroxidase antibody and thyroglobulin antibody), and cytokine panel 13). Patients completed a Quality of Health questionnaire. Statistical analysis was performed using Wilcoxon rank sum tests. RESULTS: In CAYA patients with OI or POTS and neuropathic symptoms, skin biopsy for small fiber neuropathy was abnormal in 53 %. The sample population was predominantly female and Caucasian with moderately decreased perceived quality of health. OI /POTS patients with small fiber neuropathy had a 3-fold probability of having a positive ANA or anti-thyroid antibody, suggesting an underlying autoimmune or inflammatory process. CONCLUSION: Our data suggest a link between OI and POTS and small fiber neuropathy. Small fiber neuropathy was found by skin biopsy in over half of the patients tested. OI and Postural orthostatic tachycardia patients with small fiber neuropathy expressed multiple markers suggesting an underlying autoimmune or inflammatory process. Future research will be done to evaluate the symptomatic implication of SFN and whether immune or pharmacologic manipulation can alter patient symptoms.

Symptom Score: A New Instrument to Assess Orthostatic Intolerance in Children and Adolescents.

OBJECTIVE: To develop an orthostatic intolerance symptom scoring system to assess orthostatic intolerance and then to compare the symptom score among different head-up tilt test responses. METHODS: 272 subjects (5-18 years) presenting with orthostatic intolerance symptoms finished questionnaire and head-up tilt test. According to head-up tilt test hemodynamic responses, the subjects were divided into head-up tilt test negative, vasovagal syncope, and postural tachycardia syndrome groups. RESULTS: We built up a symptom score according to the frequency of dizziness, headache, blurred vision, palpitations, chest discomfort, gastrointestinal symptoms, profuse perspiration, and syncope. The median score in postural tachycardia syndrome subjects was highest. A score of 2.5 for predicting vasovagal syncope yielded a sensitivity of 75.0% and specificity of 50.3%, a score of 5.5 for predicting postural tachycardia syndrome yielded a sensitivity of 69.7% and specificity of 72.0%. Furthermore, the median score in postural tachycardia syndrome subjects was significantly higher than that in head-up tilt test negative subjects with heart rate increment of 30-39 beats/min (P < .01). CONCLUSIONS: This suggests that the symptom score has some predictive value in head-up tilt test results, which can be served as a preliminary assessment instrument.

Clinically accessible tools for documenting the impact of orthostatic intolerance on symptoms and function in ME/CFS.

BACKGROUND: Clinical observations have indicated that hours of upright activity (HUA) reported by Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients correlated with orthostatic symptoms and impaired physical function. This study examined the relationship between HUA and orthostatic intolerance (OI). METHODS: Twenty-five female ME/CFS subjects and 25 age and race matched female healthy controls (HCs) were enrolled. Subjects reported HUA (defined as hours per day spent with feet on the floor) and completed questionnaires to assess the impact of OI on daily activities and symptoms. ME/CFS patients were categorized into those with <5 HUA and ≥5 HUA and analyzed by employment status. Data analysis used one-way ANOVA. RESULTS: ME/CFS patients had fewer HUA, worse symptoms and greater interference with daily activities due to OI than HCs. The <5 HUA ME/CFS subjects had more severe OI related symptoms than ≥5 HUA ME/CFS subjects even though OI interfered with daily activities similarly. Only 33% of ME/CFS subjects were employed and all were ≥5 HUA ME/CFS subjects with an average HUA of 8. CONCLUSIONS: ME/CFS subjects experienced more frequent and severe OI symptoms, higher interference with daily activities, and reduced ability to work than HCs. Reported HUA and assessment of OI using standardized instruments may be useful clinical tools for physicians in the diagnosis, treatment and management of ME/CFS patients.

Autonomic cardiovascular control changes in recent heart transplant recipients lead to physiological limitations in response to orthostatic challenge and isometric exercise.

PURPOSE: Heart transplantation causes denervation of the donor heart, but the consequences for cardiovascular homeostasis remain to be fully understood. The present study investigated cardiovascular autonomic control at supine rest, during orthostatic challenge and during isometric exercise in heart transplant recipients (HTxR). METHODS: A total of 50 HTxRs were investigated 7-12 weeks after transplant surgery and compared with 50 healthy control subjects. Continuous, noninvasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 60° head-up tilt and during 1 min of 30% of maximal voluntary handgrip. Plasma and urine catecholamines were assayed, and symptoms were charted. RESULTS: At supine rest, heart rate, blood pressures and total peripheral resistance were higher, and stroke volume and end diastolic volume were lower in the HTxR group. During tilt, heart rate, blood pressures and total peripheral resistance increased less, and stroke volume and end diastolic volume decreased less. During handgrip, heart rate and cardiac output increased less, and stroke volume and end diastolic volume decreased less. Orthostatic symptoms were similar across the groups, but the HTxRs complained more of pale and cold hands. CONCLUSION: HTxRs are characterized by elevated blood pressures and total peripheral resistance at supine rest as well as attenuated blood pressures and total peripheral resistance responses during orthostatic challenge, possibly caused by low-pressure cardiopulmonary baroreceptor denervation. In addition, HTxRs show attenuated cardiac output response during isometric exercise due to efferent sympathetic denervation. These physiological limitations might have negative functional consequences.

Orthostatic intolerance in chronic fatigue syndrome.

BACKGROUND: Orthostatic intolerance (OI) is a significant problem for those with chronic fatigue syndrome (CFS). We aimed to characterize orthostatic intolerance in CFS and to study the effects of exercise on OI. METHODS: CFS (n = 39) and control (n = 25) subjects had recumbent and standing symptoms assessed using the 20-point, anchored, ordinal Gracely Box Scale before and after submaximal exercise. The change in heart rate (ΔHR ≥ 30 bpm) identified Postural Orthostatic Tachycardia Syndrome (POTS) before and after exercise, and the transient, exercise-induced postural tachycardia Stress Test Activated Reversible Tachycardia (START) phenotype only after exercise. RESULTS: Dizziness and lightheadedness were found in 41% of recumbent CFS subjects and in 72% of standing CFS subjects. Orthostatic tachycardia did not account for OI symptoms in CFS. ROC analysis with a threshold ≥ 2/20 on the Gracely Box Scale stratified CFS subjects into three groups: No OI (symptoms < 2), Postural OI (only standing symptoms ≥ 2), and Persistent OI (recumbent and standing symptoms ≥ 2). CONCLUSIONS: Dizziness and Lightheadedness symptoms while recumbent are an underreported finding in CFS and should be measured when doing a clinical evaluation to diagnose orthostatic intolerance. POTS was found in 6 and START was found in 10 CFS subjects. Persistent OI had symptoms while recumbent and standing, highest symptom severity, and lability in symptoms after exercise. Trial registration The trial was registered at the following: https://clinicaltrials.gov/ct2/show/NCT03567811.

Associations Between Autonomic and Orthostatic Self-report and Physician Ratings of Orthostatic Intolerance in Youth.

PURPOSE: There is no known biological marker or physical assessment to diagnose chronic fatigue syndrome (CFS), leaving physicians to heavily rely on self-report measures regarding the symptoms associated with CFS. Common symptoms of CFS include difficulty sleeping, joint pain, headaches, sore throat, cognitive dysfunction, physical exhaustion, dizziness, and nausea. Because of the overlap among CFS symptoms and autonomic functioning, we examined the association between 2 self-report measures of orthostatic and autonomic symptoms and a physician's report of autonomic functioning (measures of changes in blood pressure and pulse) to further understand the association among autonomic functioning within individuals with symptoms of CFS. METHODS: With data from an ongoing study, we used independent t tests and Pearson correlation tests to assess the association among the orthostatic domain from the DePaul Symptom Questionnaire, Autonomic Symptom Checklist composite scores, and the physician's assessment of orthostatic intolerance obtained from a sample of 191 participants, 42 who were healthy controls. FINDINGS: No significant demographic differences were found between the CFS-like group and the healthy controls. Results indicate a significant correlation between orthostatic and autonomic functioning (r = 0.58) and a correlation with a low effect size among autonomic functioning and physician measures of orthostatic functioning (r = -0.01 to 0.29). However, fewer correlations were found between self-reported symptoms of orthostatic functioning and the physician's measures of orthostatic functioning. IMPLICATIONS: These results suggest that although orthostatic dysfunction is reported in children and adolescents with CFS-like symptoms, the physical measures of autonomic functioning in this study were unable to detect these symptoms.

Complex cardiac vagal regulation to mental and physiological stress in adolescent major depression.

BACKGROUND: Cardiovagal control is known to be reduced in major depressive disorder (MDD), however, the neurocardiac reflex control to distinct types of stressors is still unclear. We aimed to study parasympathetically mediated cardiac reflex functioning in response to mental and physiological stressors using heart rate variability (HRV) linear and nonlinear analysis in adolescent MDD. METHODS: We examined 60 adolescents (40 girls) with MDD (age 14.9 ±â€¯0.3 years) and 60 age and gender-matched controls. ECG was continuously recorded during stress protocol: baseline, Go/NoGo test, recovery, supine position, and orthostasis. Evaluated HRV linear and nonlinear indices: RR interval, pNN50, rMSSD, HF-HRV, Poincaré plot (SD1), symbolic dynamics 2UV%. Cardiovagal reactivity expressed as percentual change (%) was calculated in response to both stressors. RESULTS: In each phase of stress protocol, the MDD group had significantly reduced HRV parameters compared to controls, except for symbolic dynamics index 2UV% in supine position. The reactivity of HRV indices was significantly greater in response to orthostasis in MDD compared to controls. No significant differences were found in response to Go/NoGo test. LIMITATIONS: The smoking status and the menstrual cycle phase potentially affecting the HRV parameters were not monitored. Future research is needed to expand a sample size with respect to sex and to study neurocardiac response to other different stressors in MDD. CONCLUSIONS: This study revealed reduced resting cardiovagal regulation and greater vagal withdrawal indicating abnormal neurocardiac reflex functioning to physiological stressor (orthostasis) in adolescent MDD patients. Nonlinear HRV analysis was sensitive to detect cardiac-linked regulatory differences in adolescent depression.

Utility of Diagnostic Studies for Upper Gastrointestinal Symptoms in Children with Orthostatic Intolerance.

OBJECTIVE: To assess the utility of gastrointestinal (GI) diagnostic studies in the evaluation of patients with orthostatic intolerance. STUDY DESIGN: Medical records of 103 consecutive children/young adults with orthostatic intolerance and gastrointestinal symptoms were reviewed. All patients had undergone antroduodenal manometry in conjunction with the tilt table test, autonomic testing, and upper gastrointestinal endoscopy (EGD). A gastric emptying study (GES) was performed in 81 patients. RESULTS: The median age of the cohort was 17 years (IQR, 15-19) with a female predominance (females:males, 3:1). As expected, the tilt table test was abnormal in all patients. Antroduodenal manometry was abnormal in 83 of 103 patients (81%), showing neurogenic intestinal dysmotility in 50%, rumination in 20%, and visceral hyperalgesia in 10%. The GES results were abnormal in 23 of 81 patients (28.4%), mostly (21 of 23) with delayed GES. None of the tilt table test or autonomic results were predictive of abnormal antroduodenal manometry or GES. Analysis of EGD biopsy samples revealed nonspecific esophagitis and/or gastritis in 16 of 103 patients (15%). CONCLUSIONS: Antroduodenal manometry with the tilt table test were the most insightful investigations in adolescents and young adults with orthostatic intolerance and gastrointestinal symptoms. GES and EGD provided limited information. Gastrointestinal symptoms were related more to functional rather than mucosal or organic etiologies, suggesting a limited role of endoscopy alone in evaluating patients with orthostatic intolerance presenting with gastrointestinal symptoms.

Intracranial compliance is associated with symptoms of orthostatic intolerance in chronic fatigue syndrome.

Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion. The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity. Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest. Forty patients with CFS and 10 age and gender matched controls were scanned. Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p < .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion. There were no significant differences between the groups in intracranial compliance or perfusion. In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS.

Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is clinically defined and characterised by persistent disabling tiredness and exertional malaise, leading to functional impairment. METHODS: This study introduces the weighted standing time (WST) as a proxy for ME/CFS severity, and investigates its behaviour in an Australian cohort. WST was calculated from standing time and subjective standing difficulty data, collected via orthostatic intolerance assessments. The distribution of WST for healthy controls and ME/CFS patients was correlated with the clinical criteria, as well as pathology and cytokine markers. Included in the WST cytokine analyses were activins A and B, cytokines causally linked to inflammation, and previously demonstrated to separate ME/CFS from healthy controls. Forty-five ME/CFS patients were recruited from the CFS Discovery Clinic (Victoria) between 2011 and 2013. Seventeen healthy controls were recruited concurrently and identically assessed. RESULTS: WST distribution was significantly different between ME/CFS participants and controls, with six diagnostic criteria, five analytes and one cytokine also significantly different when comparing severity via WST. On direct comparison of ME/CFS to study controls, only serum activin B was significantly elevated, with no significant variation observed for a broad range of serum and urine markers, or other serum cytokines. CONCLUSIONS: The enhanced understanding of standing test behaviour to reflect orthostatic intolerance as a ME/CFS symptom, and the subsequent calculation of WST, will encourage the greater implementation of this simple test as a measure of ME/CFS diagnosis, and symptom severity, to the benefit of improved diagnosis and guidance for potential treatments.

Emotional orienting during interoceptive threat in orthostatic intolerance: Dysautonomic contributions to psychological symptomatology in the postural tachycardia syndrome and vasovagal syncope.

Cognitive and emotional processes are influenced by interoception (homeostatic somatic feedback), particularly when physiological arousal is unexpected and discrepancies between predicted and experienced interoceptive signals may engender anxiety. Due to the vulnerability for comorbid psychological symptoms in forms of orthostatic intolerance (OI), this study investigated psychophysiological contributions to emotional symptomatology in 20 healthy control participants (13 females, mean age 36 ±â€¯8 years), 20 postural tachycardia syndrome (PoTS) patients (18 females, mean age 38 ±â€¯13 years) and 20 vasovagal syncope (VVS) patients (15 females, mean age 39 ±â€¯12 years). We investigated indices of emotional orienting responses (OR) to randomly presented neutral, pleasant and unpleasant images in the supine position and during the induced interoceptive threat of symptom provocation of head-up tilt (HUT). PoTS and VVS patients produced greater indices of emotional responsivity to unpleasant images and, to a lesser degree, pleasant images, during interoceptive threat. Our findings are consistent with biased deployment of response-focused emotion regulation (ER) while patients are symptomatic, providing a mechanistic underpinning of how pathological autonomic overexcitation predisposes to anxiogenic traits in PoTS and VVS patients. This hypothesis may improve our understanding of why orthostasis exacerbates cognitive symptoms despite apparently normal cerebral autoregulation, and offer novel therapeutic targets for behavioural interventions aimed at reducing comorbid cognitive-affective symptoms in PoTS and VVS.

The etiologic relation between disequilibrium and orthostatic intolerance in patients with myalgic encephalomyelitis (chronic fatigue syndrome).

BACKGROUND: Orthostatic intolerance (OI) causes a marked reduction in the activities of daily living in patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. Most symptoms of OI are thought to be related to cerebral hypo-perfusion and sympathetic activation. Because postural stability is an essential element of orthostatic tolerance, disequilibrium may be involved in the etiology of OI. METHODS AND RESULTS: The study comprised 44 patients with ME (men, 11 and women, 33; mean age, 37±9 years), who underwent neurological examinations and 10-min standing and sitting tests. Symptoms of OI were detected in 40 (91%) patients and those of sitting intolerance were detected in 30 (68%). Among the 40 patients with OI, disequilibrium with instability on standing with their feet together and eyes shut, was detected in 13 (32.5%) patients and hemodynamic dysfunction during the standing test was detected in 19 (47.5%); both of these were detected in 7 (17.5%) patients. Compared with 31 patients without disequilibrium, 13 (30%) patients with disequilibrium more prevalently reported symptoms during both standing (100% vs. 87%, p=0.43) and sitting (92% vs. 58%, p=0.06) tests. Several (46% vs. 3%, p<0.01) patients failed to complete the 10-min standing test, and some (15% vs. 0%, p=0.15) failed to complete the 10-min sitting test. Among the seven patients with both hemodynamic dysfunction during the standing test and disequilibrium, three (43%) failed to complete the standing test. Among the 6 patients with disequilibrium only, 3 (50%) failed while among the 12 patients with hemodynamic dysfunction only, including 8 patients with postural orthostatic tachycardia, none (0%, p=0.02) failed. CONCLUSIONS: Patients with ME and disequilibrium reported not only OI but also sitting intolerance. Disequilibrium should be recognized as an important cause of OI and appears to be a more influential cause for OI than postural orthostatic tachycardia in patients with ME.

Improvement in low upright baroreflex sensitivity is associated with positive clinical effect of orthostatic training.

AIM: To assess the clinical efficacy of orthostatic training (OT) and its effect on the autonomic activity. METHODS: OT was performed in 38 patients (13 males, age 36.4 ± 15.2 years). Baroreflex sensitivity (BRS), heart rate variability, and quality of life (SF 36) were assessed before and after 6 months of OT. Patients with no recurrence of syncope and reduction of the presyncope number to one-third or less were classified as responders. RESULTS: Compliance to OT was low. Only 55% (38 from 69 patients) completed the training programme; 28 patients were responders (74%) and 10 patients were nonresponders. Before OT, BRS in upright position was lower in responders than in nonresponders (sitting: 8.05 ± 3.94 ms/mm Hg vs 12.51 ± 5.3 ms/mm Hg, P = 0.04, standing: 5.08 ± 2.34 ms/mm Hg vs 7.54 ± 2.16 ms/mm Hg, P = 0.02). After OT, BRS increased in responders (sitting: 8.05 ± 3.94 ms/mm Hg to 9.31 ± 4.49 ms/mm Hg, P = 0.05; standing: 5.08 ± 2.34 ms/mm Hg to 5.96 ± 2.38 ms/mm Hg, P = 0.03). No differences in supine BRS were observed. In responders, low frequency (LF) and high frequency (HF) power in sitting and standing positions significantly increased after OT (P < 0.05). In nonresponders, there was no significant rise in BRS, LF, and HF after OT. A significant increase in quality of life was noted in responders, but not in nonresponders. CONCLUSIONS: OT reduced symptoms in 74% patients who trained regularly. However, the compliance to training was low. Possible mechanism of OT is reconditioning effect on baroreceptor reactivity in upright position.

Novel insights into symptomatology of moyamoya disease in pediatric patients: survey of symptoms suggestive of orthostatic intolerance.

OBJECTIVE A specific population of young patients with moyamoya disease (MMD) persistently experience physical symptoms not attributable to focal ischemia. These symptoms, highly suggestive of orthostatic intolerance (also termed "orthostatic dysregulation"), were investigated and reported as potential determinants of quality of life in young MMD patients. METHODS Forty-six patients (6-30 years of age) were selected from a group of 122 patients who were diagnosed with MMD before 18 years of age. The authors administered a structured questionnaire consisting of 11 items based on screening checklists published in the Japanese clinical guidelines for juvenile orthostatic dysregulation in young patients. The results were tabulated, and correlations with clinical data were explored. RESULTS Thirty-seven (80%) patients (mean age 15.9 years) responded to the questionnaire. Frequent headache, vertigo/dizziness on standing, fatigue, difficulty with getting out of bed, and motion sickness were the top 5 symptoms, resulting in 57% of patients being unable to attend school. Forty-three percent of the patients demonstrated multiple symptoms suggestive of orthostatic intolerance, even as long as 5 years after revascularization surgery. The number of symptoms was inversely associated with the number of years after surgery (p = 0.028). The number of symptoms was not associated with a history of surgery, clinical presentations, vascular involvement, cerebral perfusion, brain lesions, or history of transient ischemic attacks. CONCLUSIONS The present study provided novel insight into the symptomatology of young patients with MMD. Failure to notice nonfocal physical symptoms can significantly impair quality of life in young patients with MMD even years after successful revascularization surgery. These symptoms may serve as independent clinical markers used to assess disease outcome, although the underlying mechanisms of this disease are, as of yet, unclear.

Indexes of cerebral autoregulation do not reflect impairment in syncope: insights from head-up tilt test of vasovagal and autonomic failure subjects.

PURPOSE: The study of dynamic cerebral autoregulation (CA), which adapts cerebral blood flow to arterial blood pressure (ABP) fluctuations, has been limited in orthostatic intolerance syndromes, mainly due to its stationary prerequisites hardly to meet during maneuvers to provoke syncope itself. New techniques of continuous estimates of CA could overcome this pitfall. We aimed to evaluate CA during head-up tilt test in common conditions causing syncope. METHODS: We compared three groups: eight controls; eight patients with autonomic failure due to familial amyloidotic polyneuropathy; eight patients with vasovagal syncope (VVS). ABP and cerebral blood flow velocity (CBFV) were measured with Finometer® and transcranial Doppler. We calculated cerebrovascular resistance index (CVRi), critical closing pressure (CrCP) and resistance area product (RAP), and derived CA continuously from autoregulation index [ARI(t)]. RESULTS: With HUTT, AF subjects showed a pronounced decrease in CBFV (-36 ± 17 versus -7 ± 6%, p < 0.0001), ABP (-29 ± 27 versus 7 ± 12%, p < 0.0001) and RAP (-17 ± 23 versus 3 ± 18%, p < 0.0001) but not CVRi (p = 0.110). VVS subjects showed progressive cerebral vasoconstriction prior to syncope, (reduced CBFV 19 ± 15 versus 1 ± 6, p < 0.000; increased RAP 12 ± 18 versus 2 ± 3%, p = 0.024 and CVRi 12 ± 18 versus 2 ± 3%, p = 0.005). ARI(t) increased significantly in AF patients (5.7 ± 1.2 versus 6.9 ± 1.2, p = 0.040) and VVS (5.8 ± 1.2 versus 7.3 ± 1.2, p = 0.015) in response to ABP fall during syncope. CONCLUSIONS: Our data suggest that dynamic cerebral autoregulatory response to orthostatic challenge is neither affected by autonomic dysfunction nor in neutrally mediated syncope. This study also emphasizes that RAP + CrCP model is more informative than CVRi, mainly during cerebral vasodilatory response to orthostatic hypotension.

Association of blood pressure variability with orthostatic intolerance symptoms.

The short-term blood pressure variability (BPV) reflects autonomic regulatory mechanisms. However, the influence of BPV in orthostatic intolerance (OI) is unknown. Herein, we assessed BPV profiles in patients with OI and determined their association with orthostatic symptoms. In this cross-sectional study, we prospectively enrolled 126 patients presenting with OI at the Seoul National University Hospital from December 2014 to August 2016. Among them, those with other neurological diseases (n = 8) and insufficient BP measurements (n = 15) were excluded. The degree of OI symptoms were measured using the self-administered orthostatic intolerance questionnaire (OIQ). All patients underwent ambulatory BP monitoring and we calculated the standard deviation and coefficient of variation as a measure of BPV. The mean age was 48.6 years and the average of the total OIQ score was 11.6. The severe OI group had higher BPV values than the mild group, although mean BP profiles did not differ significantly. Correlation analysis demonstrated that the orthostatic symptoms were positively correlated with diastolic BPV for the total and awake periods. Multiple linear regression analysis revealed that diastolic BPV (B = 0.46, p = 0.031) and current smoking (B = 4.687, p = 0.018) were independent factors for higher OI symptom scores after adjusting for covariates. The results of the current study demonstrated that a positive correlation exists between BPV and OI symptoms. Further studies are required to confirm the present findings and understand the neural mechanisms contributing to the excessive BPV in patients with OI.

The effects of body weight status on orthostatic intolerance and predisposition to noncardiac syncope.

Orthostatic intolerance (OI) is frequently the mechanism underlying the occurrence of noncardiac syncope (NCS) and is associated with substantial risk for injury. Body weight status appears to be a modifier of orthostatic responses and possibly influences the propensity to NCS. The majority of cross-sectional studies have found that the lower the body mass index (BMI) the greater the predisposition to OI is, accompanied with both down-regulation of sympathetic nervous system activity and up-regulation of parasympathetic nervous system activity. These changes appear to occur across the whole spectrum of BMI values from underweight to obesity, while they may be associated more strongly with central body fat than total body fat. Weight loss following bariatric surgery has been consistently found to increase OI, attributed first to the effects of weight loss per se, second to the specific type of surgical procedure and third to the potential postoperative autonomic neuropathy due to vitamin deficiency. The increased OI following bariatric surgery renders this intervention not easily tolerable for the affected individuals, mandating increased fluid and salt intake, pharmacological measures or surgical adjustments to attenuate OI. All future studies investigating orthostatic responses and NCS should implement a matching of the population arms for BMI and ideally for body fat.

Reduced Systolic Volume: Main Pathophysiological Mechanism in Patients with Orthostatic Intolerance? / Volume Sistólico Reduzido: Mecanismo Fisiopatológico Principal em Pacientes com Intolerância Ortostática?

Abstract Background: Orthostatic intolerance patients' pathophysiological mechanism is still obscure, contributing to the difficulty in their clinical management. Objective: To investigate hemodynamic changes during tilt test in individuals with orthostatic intolerance symptoms, including syncope or near syncope. Methods: Sixty-one patients who underwent tilt test at - 70° in the phase without vasodilators were divided into two groups. For data analysis, only the first 20 minutes of tilting were considered. Group I was made up of 33 patients who had an increase of total peripheral vascular resistance (TPVR) during orthostatic position; and Group II was made up of 28 patients with a decrease in TPVR (characterizing insufficient peripheral vascular resistance). The control group consisted of 24 healthy asymptomatic individuals. Hemodynamic parameters were obtained by a non-invasive hemodynamic monitor in three different moments (supine position, tilt 10' and tilt 20') adjusted for age. Results: In the supine position, systolic volume (SV) was significantly reduced in both Group II and I in comparison to the control group, respectively (66.4 ±14.9 ml vs. 81.8±14.8 ml vs. 101.5±24.2 ml; p<0.05). TPVR, however, was higher in Group II in comparison to Group I and controls, respectively (1750.5± 442 dyne.s/cm5 vs.1424±404 dyne.s/cm5 vs. 974.4±230 dyne.s/cm5; p<0.05). In the orthostatic position, at 10', there was repetition of findings, with lower absolute values of SV compared to controls (64.1±14.0 ml vs 65.5±11.3 ml vs 82.8±15.6 ml; p<0.05). TPVR, on the other hand, showed a relative drop in Group II, in comparison to Group I. Conclusion: Reduced SV was consistently observed in the groups of patients with orthostatic intolerance in comparison to the control group. Two different responses to tilt test were observed: one group with elevated TPVR and another with a relative drop in TPVR, possibly suggesting a more severe failure of compensation mechanisms.

Resumo Fundamento: O mecanismo fisiopatológico de pacientes com intolerância ortostática ainda é obscuro, contribuindo para a dificuldade no manejo clínicos desses pacientes. Objetivo: Investigar as alterações hemodinâmicas durante teste de inclinação (tilt teste) em indivíduos com sintomas de intolerância ortostática, incluindo síncope ou pré-síncope. Métodos: Sessenta e um pacientes, com tilt teste a 70º negativo na fase livre de vasodilatador, foram divididos em dois grupos. Para análise dos dados foram considerados apenas os primeiros 20 minutos de inclinação. Grupo I (33 pacientes) que tiveram elevação da resistência vascular periférica total (RVPT) durante posição ortostática e Grupo II (28 pacientes) com queda da RVPT (caracterizando insuficiência de resistência vascular periférica). O grupo controle consistia de indivíduos saudáveis e assintomáticos (24 indivíduos). Os parâmetros hemodinâmicos foram obtidos por um monitor hemodinâmico não invasivo em 3 momentos distintos (posição supina, tilt 10' e tilt 20'), ajustados para idade. Resultados: Na posição supina, o volume sistólico (VS) foi significantemente reduzido tanto no Grupo II quanto no I, quando comparado ao do Grupo controle, respectivamente (66,4 ±14,9 ml vs. 81,8±14,8 ml vs. 101,5±24,2 ml; p<0,05.) A RVPT, no entanto, foi mais elevada no Grupo II, quando comparada a do Grupo I e controles, respectivamente (1750,5± 442 dyne.s/cm5 vs.1424±404 dyne.s/cm5 vs. 974,4±230 dyne.s/cm5; p<0,05). Na posição ortostática, aos 10', houve repetição dos achados, com valores absolutos inferiores de VS Comparado aos controles (64,1±14,0 ml vs 65,5±11,3 ml vs 82,8±15,6 ml; p<0,05). A RVPT, todavia, apresentou queda relativa no Grupo II comparado ao I. Conclusão: Volume sistólico reduzido foi consistentemente observado nos grupos de pacientes com intolerância ortostática, quando comparado ao grupo controle. Foram observadas duas respostas distintas ao teste de inclinação: um grupo com elevação de RVPT e outro com queda relativa desta, indicando, possivelmente, falência mais acentuada dos mecanismos de compensação.

Orthostatic intolerance and autonomic dysfunction following bariatric surgery: A retrospective study and review of the literature.

The prevalence and costs of the obesity epidemic and obesity-related conditions, including diabetes mellitus, is consistently increasing worldwide. Bariatric medicine is attempting to address this with weight loss and exercise programmes, and with increasing frequency, various forms of bariatric surgery. There has been considerable success reported after bariatric surgery but not without. We describe 14 patients with orthostatic intolerance (OI) post bariatric surgery. We report on OI (postural dizziness, palpitations and fainting), the results of cardiovascular autonomic testing and the associated and/or causative findings as well as reviewing the literature to consider the possible mechanisms. Comprehensive autonomic testing revealed that 35.7% (Buchwald et al., 2004) of these patients fulfilled the criteria for the Postural Tachycardia Syndrome (PoTS), 57.1% (Cremieux et al., 2008) had low levels of basal BP and 42.9% (Cammisotto & Bendayan, 2007) patients were presyncopal and 14.3% (Billakanty et al., 2008) experienced syncope. We propose that the incidence of OI post-bariatric surgery is higher than considered, that certain cohorts may be more susceptible to complications, and that further research is needed to identify the prevalence and, ideally anticipate occurrence. With the increasing prevalence of obesity and required clinical interventions, further understanding of the pathophysiological processes causing autonomic dysfunction after bariatric interventions will aid management, which may differ in those with an underlying disposition to autonomic involvement, such as diabetics, in whom such procedures are increasingly used.