Cerebral Blood Flow in Orthostatic Intolerance

Abstract:

Cerebral blood flow (CBF) is vital for delivering oxygen and nutrients to the brain. Many forms of orthostatic intolerance (OI) involve impaired regulation of CBF in the upright posture, which results in disabling symptoms that decrease quality of life. Because CBF is not easy to measure, rises in heart rate or drops in blood pressure are used as proxies for abnormal CBF. These result in diagnoses such as postural orthostatic tachycardia syndrome and orthostatic hypotension. However, in many other OI syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and long COVID, heart rate and blood pressure are frequently normal despite significant drops in CBF. This often leads to the incorrect conclusion that there is nothing hemodynamically abnormal in these patients and thus no explanation or treatment is needed. There is a need to measure CBF, as orthostatic hypoperfusion is the shared pathophysiology for all forms of OI. In this review, we examine the literature studying CBF dysfunction in various syndromes with OI and evaluate methods of measuring CBF including transcranial Doppler ultrasound, extracranial cerebral blood flow ultrasound, near infrared spectroscopy, and wearable devices.

Source: Khan MS, Miller AJ, Ejaz A, Molinger J, Goyal P, MacLeod DB, Swavely A, Wilson E, Pergola M, Tandri H, Mills CF, Raj SR, Fudim M. Cerebral Blood Flow in Orthostatic Intolerance. J Am Heart Assoc. 2025 Feb 3:e036752. doi: 10.1161/JAHA.124.036752. Epub ahead of print. PMID: 39895557. https://www.ahajournals.org/doi/10.1161/JAHA.124.036752 (Full text)

Tetrahydrobiopterin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Friend or Foe?

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a chronic multisystem disease characterized by severe muscle fatigue, pain, dizziness, and brain fog. The two most common symptoms are post-exertional malaise (PEM) and orthostatic intolerance (OI). ME/CFS patients with OI (ME+OI) suffer from dizziness or faintness due to a sudden drop in blood pressure while maintaining an upright posture. Clinical research has demonstrated that patients with OI display severe cardiovascular abnormalities resulting in reduced effective blood flow in the cerebral blood vessels. However, despite intense investigation, it is not known why the effective cerebral blood flow is reduced in OI patients. Based on our recent findings, we observed that tetrahydrobiopterin (BH4) metabolism was highly dysregulated in ME+OI patients. In the current review article, we attempted to summarize our recent findings on BH4 metabolism to shed light on the molecular mechanisms of OI.

Source: Rahman AFMT, Benko A, Bulbule S, Gottschalk CG, Arnold LA, Roy A. Tetrahydrobiopterin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Friend or Foe? Biomolecules. 2025 Jan 10;15(1):102. doi: 10.3390/biom15010102. PMID: 39858496; PMCID: PMC11763651. https://pmc.ncbi.nlm.nih.gov/articles/PMC11763651/ (Full text)

Provocation of brachial plexus and systemic symptoms during the elevated arm stress test in individuals with myalgic encephalomyelitis/chronic fatigue syndrome or idiopathic chronic fatigue

Abstract:

Background: We have noted that some adolescents and young adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) report difficulty with arms-overhead activities, suggestive of brachial plexus dysfunction or thoracic outlet syndrome (TOS). In the TOS literature, diagnostic maneuvers focus on the provocation of upper limb symptoms (arm fatigue and heaviness, paresthesias, neck and upper back pain), but not on elicitation of systemic symptoms.

Objectives: To estimate the proportion of patients with fatiguing illness who experience local and systemic symptoms during a common maneuver used in evaluating TOS-the elevated arm stress test (EAST).

Methods: Patients were eligible for this retrospective study if they had been referred to the Johns Hopkins Chronic Fatigue Clinic between January 2020 and July 2023 and (a) reported difficulty maintaining arms-overhead postures, (b) were evaluated with an abbreviated one-minute EAST, and (c) had not undergone surgery in the upper limb, neck, or skull base. Modified EAST procedure: patients sat with their arms in a “hands up” or “candlestick” position while opening and closing their hands every 2-3 s repeatedly for 1 min, rather than the customary 3 min. The test was considered abnormal for local symptoms if the participant experienced pain, fatigue, heaviness, paresthesias, warmth or tremulousness in the upper limb, shoulder, neck, head, or upper back. The test was considered abnormal for systemic symptoms if the participant experienced overall fatigue, cognitive fogginess, lightheadedness, racing heart, diaphoresis, dyspnea, overall warmth, or nausea.

Results: Of 154 patients evaluated during the study period, 64 (42%) met the eligibility criteria (61/64 female, median age 18 years [range, 13 to 50]). Of the 64, 50 (78%) had ME/CFS, 13 (20%) had idiopathic chronic fatigue with associated orthostatic intolerance (OI), and one had idiopathic chronic fatigue without OI. Of the 64, 58% had evidence of joint hypermobility. Local symptoms were provoked by EAST in 62/64 (97%) within a median of 20 s. During EAST, 26/64 (41%) reported systemic symptoms (1 had only systemic but no upper limb symptoms), most commonly lightheadedness (19%) and generalized fatigue (11%).

Conclusions: Even with an abbreviated test duration, the EAST maneuver provoked local and systemic symptoms in a substantial proportion of patients with chronic fatigue, OI, and ME/CFS who had reported difficulty with arms-overhead postures. Further studies are needed to explore the prevalence of brachial plexus or TOS symptoms in unselected individuals with ME/CFS or OI, and the proportion with systemic symptoms during and after EAST.

Source: Edwards CC 3rd, Byrnes JM, Broussard CA, Azola AM, Swope ME, Marden CL, Swope RL, Lum YW, Violand RL, Rowe PC. Provocation of brachial plexus and systemic symptoms during the elevated arm stress test in individuals with myalgic encephalomyelitis/chronic fatigue syndrome or idiopathic chronic fatigue. J Transl Med. 2025 Jan 22;23(1):106. doi: 10.1186/s12967-025-06137-7. PMID: 39844172; PMCID: PMC11752803. https://pmc.ncbi.nlm.nih.gov/articles/PMC11752803/ (Full text)

Postural orthostatic tachycardia syndrome and other common autonomic disorders are not functional neurologic disorders

Introduction:

In the past 4 years of COVID-19 and Long COVID, a renewed interest in postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders brought to light a common misconception that these disorders are based in or are associated with functional neurologic disorder (FND). Recently, one narrative review attempted to link autonomic disorders and autonomic nervous system dysfunction with symptoms of FND (1). Others have similarly suggested that Long COVID may be based in functional or somatic etiology (25). As medical professionals with expertise in autonomic disorders, we would like to emphasize the distinction between autonomic disorders, autonomic symptoms and FND in order to ensure that appropriate diagnostic and therapeutic pathways are implemented by clinicians.

Source: Blitshteyn S, Treisman GJ, Ruhoy IS, Saperstein DS, Schofield JR, Goodman BP, Davenport TE, Cutchins AC and Grubb BP (2024) Postural orthostatic tachycardia syndrome and other common autonomic disorders are not functional neurologic disorders. Front. Neurol. 15:1490744. doi: 10.3389/fneur.2024.1490744 https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1490744/full (Full text)

Overlapping conditions in Long COVID at a multisite academic center

Abstract:

Background: Many patients experience persistent symptoms after COVID-19, a syndrome referred to as Long COVID (LC). The goal of this study was to identify novel new or worsening comorbidities self-reported in patients with LC.

Methods: Patients diagnosed with LC (n = 732) at the Mayo Long COVID Care Clinic in Rochester, Minnesota and Jacksonville, Florida were sent questionnaires to assess the development of new or worsening comorbidities following COVID-19 compared to patients with SARS-CoV-2 that did not develop LC (controls). Both groups were also asked questions screening for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), generalized joint hypermobility (GJH) and orthostatic intolerance. 247 people with LC (33.7%) and 40 controls (50%) responded to the surveys.

Results: In this study LC patients averaged 53 years of age and were predominantly White (95%) women (75%). The greatest prevalence of new or worsening comorbidities following SARS-CoV-2 infection in patients with LC vs. controls reported in this study were pain (94.4% vs. 0%, p < 0.001), neurological (92.4% vs. 15.4%, p < 0.001), sleep (82.8% vs. 5.3%, p < 0.001), skin (69.8% vs. 0%, p < 0.001), and genitourinary (60.6% vs. 25.0%, p = 0.029) issues. 58% of LC patients screened positive for ME/CFS vs. 0% of controls (p < 0.001), 27% positive for GJH compared to 10% of controls (p = 0.026), and a positive average score of 4.0 on orthostatic intolerance vs. 0 (p < 0.001). The majority of LC patients with ME/CFS were women (77%).

Conclusion: We found that comorbidities across 12 surveyed categories were increased in patients following SARS-CoV-2 infection. Our data also support the overlap of LC with ME/CFS, GJH, and orthostatic intolerance. We discuss the pathophysiologic, research, and clinical implications of identifying these conditions with LC.

Source: Grach SL, Dudenkov DV, Pollack B, Fairweather D, Aakre CA, Munipalli B, Croghan IT, Mueller MR, Overgaard JD, Bruno KA, Collins NM, Li Z, Hurt RT, Tal MC, Ganesh R, Knight DTR. Overlapping conditions in Long COVID at a multisite academic center. Front Neurol. 2024 Oct 25;15:1482917. doi: 10.3389/fneur.2024.1482917. PMID: 39524912; PMCID: PMC11543549. https://pmc.ncbi.nlm.nih.gov/articles/PMC11543549/ (Full text)

Hypocapnic cerebral hypoperfusion: A biomarker of orthostatic intolerance

Abstract:

The objective of the study was to identify markers of hypocapnic cerebral hypoperfusion (HYCH) in patients with orthostatic intolerance (OI) without tachycardia and without orthostatic hypotension. This single center, retrospective study included OI patients referred for autonomic evaluation with the 10 min tilt test. Heart rate, end-tidal CO2 (ET-CO2), blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery were monitored. HYCH was defined by: (1) Symptoms of OI; (2) Orthostatic hypocapnia (low ET-CO2); (3) Abnormal decline in orthostatic CBFv due to hypocapnia; 4) Absence of tachycardia, orthostatic hypotension, or other causes of low CBFv or hypocapnia.

Sixteen subjects met HYCH criteria (15/1 women/men, age 38.5±8.0 years) and were matched by age and gender to postural tachycardia patients (POTS, n = 16) and healthy controls (n = 16). During the tilt, CBFv decreased more in HYCH (-22.4±7.7%, p<0.0001) and POTS (-19.0±10.3%, p<0.0001) compared to controls (-3.0±5.0%). Orthostatic ET-CO2 was lower in HYCH (26.4±4.2 (mmHg), p<0.0001) and POTS (28.6±4.3, p<0.0001) compared to controls (36.9 ± 2.1 mmHg). Orthostatic heart rate was normal in HYCH (89.0±10.9 (BPM), p<0.08) and controls (80.8 ±11.2), but was higher in POTS (123.7±11.2, p<0.0001). Blood pressure was normal and similar in all groups.

It is concluded that both HYCH and POTS patients have comparable decrease in CBFv which is due to vasoconstrictive effect of hypocapnia. Blood flow velocity monitoring can provide an objective biomarker for HYCH in OI patients without tachycardia.

Source: Novak P. Hypocapnic cerebral hypoperfusion: A biomarker of orthostatic intolerance. PLoS One. 2018 Sep 26;13(9):e0204419. doi: 10.1371/journal.pone.0204419. PMID: 30256820; PMCID: PMC6157889. https://pmc.ncbi.nlm.nih.gov/articles/PMC6157889/ (Full text)

Expanded autonomic testing helps to pinpoint cases of orthostatic intolerance

News:

Using expanded, state-of-the-art capabilities in autonomic testing, Peter Novak, MD, PhD, Chief of the Division of Autonomic Neurology in the Department of Neurology, is driving better understanding of hard-to-diagnose patients with orthostatic intolerance.

The debilitating condition is among the most common neurological conditions affecting women in the United States ages 35 or younger. While knowledge of orthostatic intolerance has become more nuanced in recent years, diagnosing some patients’ symptoms when changing from lying to standing (dizziness, weakness and shortness of breath, with or without rapid heartbeat) has remained elusive.

The identification of postural orthostatic tachycardia syndrome (POTS) in the early 1990s led to clearer diagnosis of many patients. But the syndrome, by definition, excludes those who do not experience tachycardia. To address their symptoms, these patients sometimes are prescribed antianxiety or antidepressant medications.

To better understand these patients, Dr. Novak turned to continuous monitoring of end tidal CO2 and CBFv (cerebral blood flow velocity). As the technologies became available for clinical use, Novak added them to routine testing. The results led him to identify two new syndromes relating to orthostatic dizziness.

“We can now diagnose people who were previously thought to have psychiatric illness or had no diagnosis at all,” says Dr. Novak, of the Department of Neurology, one of only a few departments in the United States that has a Division of Autonomic Neurology.

In addition to continuous monitoring of heart rate and blood pressure that is standard for Valsalva maneuver and tilt-table tests, Dr. Novak’s Autonomic Testing Lab, located at Brigham and Women’s Faulkner Hospital, also measures and interprets end tidal CO2 and CBFv during these tests. Through testing, he has characterized two new syndromes:

  • Hypocapnic cerebral hypoperfusion (HYCH) is a novel syndrome of low CBFv that Novak described in late 2018 in PLoS ONE, as a biomarker of orthostatic intolerance. HYCH can be detected during a tilt test, in patients without orthostatic tachycardia, hypotension, arrhythmia, vascular abnormalities or other causes of abnormal orthostatic CBFv. “This is POTS without the T,” explains Dr. Novak. “These people have normal BP and normal heart rate. But they have the same low blood flow as in POTS due to vasoconstrictive effect of hypocapnia (low end tidal CO2). This is the main reason to monitor blood flow. Otherwise you can miss what is going on with this the patient, and the patient could be misdiagnosed as having a psychiatric illness.” The Autonomic Testing Lab currently sees at last two patients each month who meet the criteria of HYCH. Treatment is similar to that of patients with POTS (combination of exercise, diet and medication for more severe cases), since HYCH and POTS are probably on a spectrum of the same disorder.
  • Orthostatic Cerebral Hypoperfusion Syndrome (OCHOS) is a syndrome of orthostatic intolerance associated with low CBFv that Dr. Novak first described in 2016. In this syndrome, the orthostatic cerebral blood flow is reduced while all other variables are normal. OCHOS can be disabling. Many patients respond to volume expansion or cerebral vasodilators, but the optimal therapy has yet to be found.

Both OCHOS and HYCH are described among the 100 case studies in Dr. Novak’s recently published book Autonomic Testing, (Oxford University Press, April 2019), intended as a practical manual for performing and interpreting autonomic testing. Each case study includes the testing evaluation, results (with visual images to guide test interpretations) and recommendations for treatment and follow-up. Nearly all cases show results of the newer techniques of continuous CBFv and CO2 monitoring concurrent with traditional heart rate and blood pressure testing. “Together, they are more valuable than separately,” Dr. Novak explains.

The combination of classic autonomic tests (Valsalva maneuver, deep breathing and tilt test) enhanced by using of continuous CBFv and CO2 monitoring together make up “the Brigham Protocol.” In addition, the protocol includes non-invasive skin biopsies, now routinely performed in the lab to assess direct small fiber damage, which may indicate inflammation that is treatable. “We call it autonomic testing, but it is more than that at our institution,” says Dr. Novak.

Since 2015, the Autonomic Testing Lab has performed autonomic testing on approximately 1,300 people, about half of them for orthostatic symptoms, says Dr. Novak.

For questions about autonomic testing or if you have a patient who would benefit from autonomic testing, learn more here.

Dysregulation of tetrahydrobiopterin metabolism in myalgic encephalomyelitis/chronic fatigue syndrome by pentose phosphate pathway

Abstract:

Background: Tetrahydrobiopterin (BH4) and its oxidized derivative dihydrobiopterin (BH2) were found to be strongly elevated in ME/CFS patients with orthostatic intolerance (ME + OI).

Objective: However, the molecular mechanism of biopterin biogenesis is poorly understood in ME + OI subjects. Here, we report that the activation of the non-oxidative pentose phosphate pathway (PPP) plays a critical role in the biogenesis of biopterins (BH4 and BH2) in ME + OI subjects.

Research design and results: Microarray-based gene screening followed by real-time PCR-based validation, ELISA assay, and finally enzyme kinetic studies of glucose-6-phosphate dehydrogenase (G6PDH), transaldolase (TALDO1), and transketolase (TK) enzymes revealed that the augmentation of anaerobic PPP is critical in the regulations of biopterins. To further investigate, we devised a novel cell culture strategy to induce non-oxidative PPP by treating human microglial cells with ribose-5-phosphate (R5P) under a hypoxic condition of 85%N2/10%CO2/5%O2 followed by the analysis of biopterin metabolism via ELISA, immunoblot, and dual immunocytochemical analyses. Moreover, the siRNA knocking down of the taldo1 gene strongly inhibited the bioavailability of phosphoribosyl pyrophosphate (PRPP), reduced the expressions of purine biosynthetic enzymes, attenuated GTP cyclohydrolase 1 (GTPCH1), and suppressed subsequent production of BH4 and its metabolic conversion to BH2 in R5P-treated and hypoxia-induced C20 human microglia cells. These results confirmed that the activation of non-oxidative PPP is indeed required for the upregulation of both BH4 and BH2 via the purine biosynthetic pathway. To test the functional role of ME + OI plasma-derived biopterins, exogenously added plasma samples of ME + OI plasma with high BH4 upregulated inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in human microglial cells indicating that the non-oxidative PPP-induced-biopterins could stimulate inflammatory response in ME + OI patients.

Conclusion: Taken together, our current research highlights that the induction of non-oxidative PPP regulates the biogenesis of biopterins contributing to ME/CFS pathogenesis.

Source: Bulbule S, Gottschalk CG, Drosen ME, Peterson D, Arnold LA, Roy A. Dysregulation of tetrahydrobiopterin metabolism in myalgic encephalomyelitis/chronic fatigue syndrome by pentose phosphate pathway. J Cent Nerv Syst Dis. 2024 Aug 19;16:11795735241271675. doi: 10.1177/11795735241271675. PMID: 39161795; PMCID: PMC11331476. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331476/ (Full text)

Phenylephrine Alters Phase Synchronization between Cerebral Blood Velocity and Blood Pressure in Chronic Fatigue Syndrome with Orthostatic Intolerance

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neuro-cognitive 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 years) and 15 ME/CFS patients (mean age=21.8 years). All ME/CFS patients had postural tachycardia syndrome (POTS).

A 10-minute 60⁰ 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 vs. control. In ME/CFS, HUT significantly decreased CBV compared to 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. While CO2 and Acetazolamide had no effect on PhSI in ME/CFS, PE 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 ME/CFS patients, perhaps related to improved neurovascular coupling, cerebral autoregulation and maintenance of CBV.

Source: Medow MS, Stewart JM. Phenylephrine Alters Phase Synchronization between Cerebral Blood Velocity and Blood Pressure in Chronic Fatigue Syndrome with Orthostatic Intolerance. Am J Physiol Regul Integr Comp Physiol. 2024 Apr 29. doi: 10.1152/ajpregu.00071.2024. Epub ahead of print. PMID: 38682242. https://journals.physiology.org/doi/abs/10.1152/ajpregu.00071.2024 (Full text available as PDF file)

Low Vasopressin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (P4-4.006)

Abstract:

Objective: To shed light on the pathophysiology of water homeostasis in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), classified by WHO as a neurological disease (ICD 10 code G933).

Background: The complex symptomatology of ME/CFS includes signs suggesting abnormal water homeostasis and hypovolemia. Since many patients report polyuria-polydipsia, we conducted an observational series of plasma and urine osmolality as well as plasma levels of vasopressin (VP) in consecutive patients diagnosed with ME/CFS according to the Canadian Consensus Criteria.

Design/Methods: Plasma and urine osmolality (P-Osm and U-Osm, respectively) and plasma VP levels were measured in 111 patients after overnight fasting and 10-hour fluid deprivation. The clinical routine also included brain MRI and blood chemistry.

Results: Following the fluid deprivation P-Osm was above normal (>292 mOsm/kg) in 61 patients (55.0%) and U-Osm below normal (< 750 mOsm/kg) in 74 patients (66.7%). VP-levels were below the level of detection (<1.6 pg/mL) in 91 patients (82.0%). A normal level of VP in relation to their P-Osm was found in 11 patients (9.9 %). The state resembling a central type of diabetes insipidus (cDI) would in the absence of hypophyseal imaging findings and blood chemistry consistent with any other hypophyseal hormonal defect be classified as idiopathic.

Conclusions: Our findings suggest that deficiency of vasopressin secretion is a fundamental measurable part of the disease mechanisms, which may underlie a number of symptoms in ME/CFS, including the common complaint of orthostatic intolerance.

Source: Helena Huhmar, Lauri Soinne, Per Sjögren, Bo Christer Bertilson, Per Hamid Ghatan, Björn Bragée, and Olli Polo. Low Vasopressin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (P4-4.006) Neurology, April 9, 2024 issue 102 (17_supplement_1) https://doi.org/10.1212/WNL.000000000020576 https://www.neurology.org/doi/10.1212/WNL.0000000000205761