Beyond the headache: autonomic reflex dysfunction and heightened sensory sensitivity contribute to orthostatic intolerance in migraine.

Objective:We sought to determine: 1.) the relationship between headache frequency and autonomic reflexes, and 2.) mechanisms underlying orthostatic intolerance (OI) in patients with migraine.Methods:Adults with migraine (N = 30) underwent autonomic function tests summarized as the Composite Autonomic Severity Score (CASS) and vagal/adrenergic baroreflex sensitivity (BRS-V/A). Postural Orthostatic Tachycardia Syndrome (POTS) and orthostatic hypotension/hypertension were diagnosed during tilt table testing. A cold pressor test (CPT) evaluated sympathetic vasomotor function. Participants completed the Migraine Disability Assessment (MIDAS), the 2011 Fibromyalgia (FM) Survey Criteria, chronic overlapping pain condition (COPC) screener, and Compass-31.Results:Monthly headache days correlated with CASS (p = 0.001), BRS-V (p < 0.001), and the systolic blood pressure response to CPT (p = 0.003) in the expected direction with increasing ANS reflex dysfunction correlating to increasing number of headache days. During tilt testing, OI was prevalent (25/30; 83%) and reported by all patients with chronic migraine. An abnormal cardiovascular response to tilt was present in the majority (63%) of which POTS was the most common etiology (56.2%). Patients reporting OI during tilt table testing despite a normal cardiovascular response (33%) had higher FM scores (15.8 ± 3.6 vs. 7.5 ± 4.6; p < 0.01) and a greater prevalence of non-headache COPCs (88.8% versus 20.0%, p = 0.02), compared to participants who were asymptomatic during tilt.Conclusions:There are two etiologies of OI in patients with migraine: 1.) an abnormal cardiovascular response to tilt (concordant OI) and, 2.) sensory hypersensitivity (discordant OI).

When a person stands up, he or she assumes that the body will automatically make any changes necessary to compensate for the increased gravitational stress this change of position brings. Indeed, standing causes gravity to try to pull nearly one quarter of the body’s blood downward toward the lower arms, legs, and abdomen, reducing the amount of blood available to keep the brain supplied with oxygen. To maintain a constant oxygen supply to the brain and upper body, standing is normally accompanied by an automatic increase in heart rate and the force with which the heart contracts and, most important, a tightening of the blood vessels in the lower part of the body. The combination of these 3 actions pushes blood upward against the force of gravity, thereby maintaining an uninterrupted flow of blood to the brain. The aspect of the nervous system that governs these …

BackgroundNon-cephalgic symptoms including orthostatic intolerance, fatigue, and cognitive impairment, are common in patients with chronic headache disorders and may result from alterations in the autonomic nervous system. However, little is known about the function of autonomic reflexes, which regulate cardiovascular homeostasis and cerebral perfusion in patients with headache.MethodsAutonomic function testing data from patients with headache collected between January 2018 and April 2022 was retrospectively analyzed. Through review of EMR we determined headache pain chronicity and patient self-report of orthostatic intolerance, fatigue, and cognitive impairment. Composite Autonomic Severity Score (CASS), CASS subscale scores, and cardiovagal and adrenergic baroreflex sensitivities were used to quantify autonomic reflex dysfunction. Descriptive analyses (Mann-Whitney-U or χ2, as appropriate) determined associations between autonomic reflex dysfunction and POTS as well as chronic headache. Binomial logistic regression adjusted for age and sex. Spearman’s rank correlation determined the association between the total CASS score and the number of painless symptoms reported by each participant.ResultsWe identified 34 patients meeting inclusion criteria, of whom there were 16 (47.0%) with orthostatic intolerance, 17 (50.0%) with fatigue, 11 (32.4%) with cognitive complaints, and 11 (32.4%) with Postural Orthostatic Tachycardia Syndrome (POTS). The majority of participants had migraine (n = 24, 70.6%), were female (n = 23, 67.6%) and had a chronic (>15 headache days in a month) headache disorder (n = 26, 76.5%). Reduced cardiovagal baroreflex sensitivity (BRS-V) independently predicted chronic headache [aOR: 18.59 (1.16, 297.05), p = 0.039] and POTS [aOR: 5.78 (1.0, 32.5), p = 0.047]. The total CASS was correlated with the total number of non-painful features in the expected direction (r = 0.46, p = 0.007).ConclusionAbnormal autonomic reflexes may play an important role in pain chronification and the development of POTS in patients with headache.

Postural Tachycardia Syndrome from a Pediatrics Perspective

Background: Orthostatic intolerance (OI) is an important factor affecting daily functional capacity in patients with long COVID. Traditionally, most OI symptoms have been attributed to exaggerated sympathetic nervous system activation associated with postural orthostatic tachycardia syndrome (POTS). Disequilibrium, also referred to as postural instability, may contribute to the development of OI in patients with long COVID. Methods: This study evaluated 32 patients with long COVID using neurological examinations and the active 10-min standing test. Disequilibrium was assessed using the Romberg and tandem gait tests. OI was defined as the inability to complete the active 10-min standing test. Results: Seven patients (22%) were diagnosed with OI. None of them had POTS, whereas six (86%) demonstrated disequilibrium, as detected by the Romberg and/or tandem gait test. POTS was observed in eight patients (25%), none of whom had OI. Disequilibrium was observed in nine patients (28%), six of whom (67%) had OI. Multiple regression analysis revealed that disequilibrium was positively associated with OI (r = 0.64, p < 0.001), whereas POTS was inversely associated (r = -0.38, p < 0.05). After 6 weeks of oral minocycline treatment in six patients and 2 weeks of repetitive transcranial magnetic stimulation therapy following minocycline in the other one patient, symptom amelioration was reported in six patients with OI. OI concomitant with disequilibrium recovered in five of the six patients treated and tested, although one patient who experienced symptom recovery failed to undergo the repeated standing test. Conclusions: Disequilibrium, rather than POTS, was the primary determinant of OI in patients with long COVID.

Orthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (PoTS) and orthostatic hypotension (OH), are often reported in long covid, but published studies are small with inconsistent results. We sought to estimate the prevalence of objective OI in patients attending long covid clinics and healthy volunteers and associations with OI symptoms and comorbidities.Participants with a diagnosis of long covid were recruited from eightUK long covid clinics, and healthy volunteers from general population. All undertook standardized National Aeronautics and Space Administration Lean Test (NLT). Participants' history of typical OI symptoms (e.g., dizziness, palpitations) before and during the NLT were recorded.Two hundred seventy-seven long covid patients and 50 frequency-matched healthy volunteers were tested. Healthy volunteers had no history of OI symptoms or symptoms during NLT or PoTS, 10% had asymptomatic OH. One hundred thirty(47%) long covid patients had previous history of OI symptoms and 144 (52%) developed symptoms during the NLT. Forty-one(15%) had an abnormal NLT, 20 (7%) met criteria for PoTS, and 21 (8%) had OH. Of patients with an abnormal NLT, 45% had no prior symptoms of OI. Relaxing the diagnostic thresholds for PoTS from two consecutive abnormal readings to one abnormal reading during the NLT, resulted in 11% of long covid participants (an additional 4%) meeting criteria for PoTS, but not in healthy volunteers.More than half of long covid patients experienced OI symptoms during NLT and more than one in 10patients met the criteria for either PoTS or OH, half of whom did not report previous typical OI symptoms. We therefore recommend all patients attending long covid clinics are offered an NLT and appropriate management commenced.

Introduction Symptoms suggestive of autonomic nervous system (ANS) dysfunction have been previously described in patients with idiopathic hypersomnia (IH), however, objective ANS reflex testing data has not been reported. We aimed to better quantify symptoms of ANS dysfunction in a cohort of patients with IH through the use of standardized ANS reflex testing. Methods Patients diagnosed with IH based on ICSD-3 criteria using overnight video polysomnography and multiple sleep latency testing (MSLT) were consecutively enrolled in our study, regardless of ANS symptoms. All patients underwent ANS reflex testing, including measures of parasympathetic (heart rate variability with deep breathing and Valsalva ratio) and sympathetic adrenergic function (Valsalva blood pressure response and 10-minute head-up tilt at an angle of 70 degrees) with continuous blood pressure and heart rate monitoring. Eleven patients also underwent measures of sympathetic cholinergic function (quantitative sudomotor axon reflex testing). All medications that affect ANS function were held prior to ANS testing, including wake-promoting medications and sodium oxybate. Results Twenty patients with IH were enrolled. Fifty percent (10/20) were long sleepers (&amp;gt;11hrs). Mean sleep onset latency and number of sleep onset REM periods (SOREMs) on MSLT were 6.9 (± 3.1) mins and 0.2 (± 0.4), respectively. Mean duration of IH symptoms prior to the date of ANS testing was 6.3 (± 8.1) yrs. Eighty-five percent (17/20) of patients had abnormal ANS testing. Of these, 75% (15/20) had sympathetic adrenergic impairment, 64% (7/11) had sympathetic cholinergic impairment, and 5% (1/20) had parasympathetic impairment. Fifty-five percent (11/20) of patients were diagnosed with postural tachycardia syndrome (POTS), 45% (5/11) with small fiber neuropathy, 5% (1/20) with inappropriate sinus tachycardia and 15% (3/20) with neurally-mediated syncope. Seventy percent (14/20) of patients reported orthostatic intolerance regardless of autonomic diagnosis. Conclusion ANS dysfunction was common and severe in our cohort of IH patients, affecting all domains of ANS reflex testing, with more prominent impairment in sympathetic domains. POTS was the most common comorbid diagnosis, and most patients reported orthostatic intolerance. There was no association with IH disease duration, though our sample size was limited. Future studies will focus on ANS testing in larger cohorts of IH patients, specifically on shared pathophysiological mechanisms of hypersomnia and ANS dysfunction. Support (If Any)

The objective of this study was to assess hemodynamic responses and baroreflex sensitivity (BRS) indexes during Valsalva maneuver (VM) and head-up tilt (HUT) testing in orthostatic intolerance (OI). Patients with neurogenic orthostatic hypotension (NOH, n = 26), postural tachycardia syndrome (n = 26) and symptomatic OI (n = 14) were compared with healthy population (control, n = 107) and inappropriate sinus tachycardia (n = 7). Hemodynamic assessment included patterning and quantification with vagal and adrenergic BRS (BRSa/BRSa1). In NOH, cardiovagal systolic blood pressure (SBP) decrements in VM and HUT were correlated (r = 0.660, P < 0.001); a "V" pattern of VM indicated α-BRSa failure. Yet BRSa1 did not reveal changes vs. control (P > 0.05) or was not applicable in 60% of NOH. In symptomatic OI, compared with control, cardiovagal SBP decrements were larger (P < 0.05); higher BRSa1 contradicted higher adrenergic index (Composite Autonomic Severity Score). Overshoot in phase IV dipped below baseline or dropped ≥ 10 mmHg over 8 s in postural tachycardia syndrome ("N" pattern), but by 3 s in inappropriate sinus tachycardia ("M" pattern). Visualization of distinct VM patterns allows primary evaluation of autonomic dysfunction and differentiation of the various forms of OI. BRSa1 evaluation is compromised by pathological SBP patterns. VM patterning is a valuable nonpostural supplement to HUT capable of detecting and differentiating OI.

1. Talha Niaz, MBBS* 2. Kelsey Klaas, MD* 1. *Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN A 15-year-old girl presents to the clinic with frequent episodes of syncope and chronic symptoms of headaches, fatigue, body aches, and abdominal discomfort. She sustained fractures of her fourth through sixth cervical vertebra due to a gymnastics injury 4 years ago, resulting in 3 months of bed rest. During recovery, she developed new onset dizziness, palpitations, and “blacking out” of her vision on standing that were later followed by syncope. Her symptoms gradually worsened over the last 4 years. Recently, she had frequent syncopal events usually associated with upright posture with episodes characterized by brief loss of consciousness for 5 to 10 seconds and then spontaneous recovery with no convulsions, postictal state, or incontinence. Spells have occurred after, but never during, exercise. She has nonrestorative sleep, low energy, and progressive tiredness throughout the day. She has diffuse body aches and occasional knee pain on activity without joint swelling, redness, or morning stiffness. She recently developed a daily headache, which is bilateral, 4/10 in intensity, pounding or throbbing, and associated with nausea without vomiting. She also has intermittent abdominal discomfort with no diarrhea or constipation. She has had normal growth and no weight loss. On examination, she has a supine heart rate of 64 beats/min that increases to 102 beats/min after standing for 3 minutes associated with some dizziness but no significant hypotension. She has a dark red to purple discoloration of her feet on standing. She has a Beighton (hypermobility) score of 4/9. The rest of her examination, including cardiac and neurologic, is normal. She has a normal electrocardiogram, head magnetic resonance imaging, and laboratory work except for serum ferritin …

The possible association between COVID-19 and postural tachycardia syndrome

Objective: To characterize autonomic nervous system (ANS) abnormalities unique to active duty US service members and compare those findings to civilian counterparts. Background Autonomic dysfunction is increasingly recognized as a contributor to morbidity in patients with traumatic brain injury (TBI). The signature injury of Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) is TBI so the military offers a special population to study ANS dysfunction. The purpose of this study is to analyze the difference in autonomic complaints and autonomic testing results of active duty compared to civilian patients. Design/Methods: We reviewed retrospectively the records of all patients who were evaluated at a Military Medical Treatment Facility (MTF) autonomic laboratory over a 12 month period. These patients included 56 active duty military and 49 civilians. The percentage of patients who presented with orthostatic intolerance (OI) and syncope was calculated and the distribution of diagnoses was evaluated. Tests considered included the heart rate response to deep breathing, valsalva, and tilt table testing. Results: Active duty service members were most commonly referred to the autonomic laboratory for OI (N=13, 23%) and syncope (N=23, 41%). 37 (66%) had normal studies, 13 (23%) were found to have OI and four were diagnosed with postural orthostatic tachycardia syndrome (POTS). Civilians were commonly referred to the autonomic laboratory for OI (N=10, 20%) and syncope (N=20, 40%). 27 (55%) of the studies were normal, six had orthostatic intolerance, four had POTS, and four had adrenergic failure. Conclusions: Autonomic disorders are underrecognized in the military. Active duty service members with autonomic dysfunction may be classified as unfit for duty due to the rigorous nature of work in the military. ANS disorders in service members should be recognized early so they may be properly addressed and increase the service members likelihood of returning to full duty. Disclosure: Dr. Crimmins has nothing to disclose. Dr. Etienne has nothing to disclose.

Disturbances in autonomic nervous system function have been reported to occur in patients suffering from mitochondrial cytopathies. However, there is paucity of literature on the occurrence of orthostatic intolerance (OI) in these patients. We report on a series of patients diagnosed with mitochondrial cytopathy who developed features of autonomic dysfunction in the form of OI. This was a single-center report on a series of 6 patients who were followed in our clinic for orthostatic intolerance. All of these patients had a diagnosis of mitochondrial cytopathy on the basis of muscle biopsy and were being followed at a center specializing in the treatment of mitochondrial disorders. This study was approved by our local institutional review board. Each of the patients had suffered from symptoms of fatigue, palpitations, near syncope, and syncope. The diagnosis of OI was confirmed by head-up tilt test. Collected data included demographic information, presenting symptoms, laboratory data, tilt-table response, and treatment outcomes. Six patients (3 females) were identified for inclusion in this report. The mean age of the group was 48 ± 8 years (range, 40-60 years). All of these patients underwent head-up tilt table testing and all had a positive response that reproduced their clinical symptoms. Among those having an abnormal tilt-table pattern, 1 had a neurocardiogenic response, 1 had a dysautonomic response, and 4 had a postural orthostatic tachycardia response. All but 1 patient reported marked symptom relief with pharmacotherapy. The patient who failed pharmacotherapy received a dual-chamber closed-loop pacemaker and subsequently reported marked improvement in her symptoms with elimination of her syncope. Orthostatic intolerance might be a significant feature of autonomic nervous system dysfunction in patients suffering from mitochondrial cytopathy.

A UNIQUE CASE OF CONCURRENT EHLERS DANLOS SYNDROME (EDS) AND POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME (POTS) ASSOCIATED WITH ORTHOSTATIC HYPERTENSION RESPONDING TO IV FLUIDS

The clinical utility of autonomic function tests in pediatric gastroenterology is steadily evolving. The current tests available evaluate cardiac and sudomotor responses, and not direct gastrointestinal response. Therefore, when these tests are utilized in clinical practice, the results are extrapolated (in the appropriate clinical setting) to the abnormality of the gastrointestinal tract. The tests are divided into those of autonomic cardiovascular function (Cardiac response to deep breathing, Valsalva maneuver, head up tilt (HUT) table test, handgrip and cold pressor test) and those of sudomotor function (quantitative sudomotor test and thermoregulatory sweat test). Together, these two groups of tests evaluate the sympathetic adrenergic, sympathetic cholinergic, and parasympathetic cholinergic function in several organ systems, and assess for the presence or absence of a generalized autonomic neuropathy.In preparation for the testing, the subject should be well hydrated, free of caffeine and nicotine exposure, and all medications that may interfere with the response of the autonomic nervous system should be stopped about 5-half lives to 5–7 days prior to the testing date. Such medications include α(alpha)- and β(beta)-receptor agonists and antagonists, pro- and anticholinergics and mineralocorticoids, selective serotonin reuptake inhibitors, and serotonin nonselective reuptake inhibitors.Some data show altered electrical activity of the stomach in the upright position in subjects with postural tachycardia syndrome (POTS). In addition, treatment of the orthostatic intolerance in patients with POTS often benefits their gastrointestinal symptoms. Thus, there appear to be a significant physiologic relationship between orthostatic and gastrointestinal dysfunction, although the exact nature of this is yet to be elucidated.KeywordsValsalva ManeuverCold Pressor TestLower Body Negative PressureOrthostatic IntoleranceFunctional Gastrointestinal DisorderThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Received September 14, 2004; revision received January 31, 2005; accepted March 9, 2005. “We shall not cease from exploration and the end of all our exploring will be to arrive where we started and know the place for the first time” — —T.S. Eliot, Four Quartets Syncope, defined as transient loss of consciousness and postural tone with spontaneous recovery, has both challenged and perplexed physicians since the dawn of recorded time. The earliest written accounts come from Hippocrates, and the word syncope itself is derived from an old Greek term meaning “to cut short” or “interrupt.” Recurrent episodes of syncope may result from a large number of different disorders, all of which cause a transitory reduction in cerebral blood flow sufficient to disturb the normal functions of the brain. Over the last 2 decades, considerable attention has been given to types of syncope that occur due to a centrally mediated (or “reflex”) fall in systemic blood pressure, a condition that has been referred to as vasovagal (and later neurocardiogenic) syncope. However, research into the nature of this disorder revealed that it is but one aspect of a broad and varied group of disturbances in the normal functioning of the autonomic nervous system (ANS), each of which may result in orthostatic intolerance, hypotension, and ultimately syncope. Continued investigations into the nature of these similar yet different disorders has led to the development of a system of classification that attempts to more accurately reflect our understanding of these conditions and their interrelationships.1 The present system of classification has proven both functional and clinically relevant and includes a group of disorders that most investigators have thought to be principally autonomic in nature. Because both the cardiologist and the cardiac electrophysiologist frequently are expected to both diagnose and treat these conditions, the following …