Tag: orthostatic intolerance

A Continuous Oral Regimen of High-Dose Cromolyn Sodium Is Effective for Some Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients With Mast Cell Activation Syndrome

Abstract:

Our clinical experience in the last four years using oral cromolyn in patients with mast cell activation syndrome (MCAS) suggests that a continuous oral regimen of high-dose cromolyn may enhance compliance with the medication. The five patients described in this retrospective case series were given instructions to take oral cromolyn using a continuous dosing regimen, placing the entire day’s dose in an opaque bottle that is then filled with water, and sipping the solution throughout the day. If a conventional maximum dose of eight vials daily (800 mg) was tolerated but ineffective after a week, the patients were instructed to increase to 1600-2400 mg daily until reaching an optimal effect.

We report that a cromolyn dose of 1600-2400 mg daily, administered using the continuous oral dosing regimen during the day, was effective in controlling signs and symptoms of mast cell activation. All five patients benefitted from a dose of cromolyn that is higher than usual and customary recommendations, but within the safety guidelines of the original Food and Drug Administration (FDA) application. The continuous oral regimen has some theoretical advantages over four discrete doses per day, though further study is needed.

Source: Christoforou ME, van Campen LC, Visser FC, Lee CK, Lemmon SL, Rowe PC, Azola AM. A Continuous Oral Regimen of High-Dose Cromolyn Sodium Is Effective for Some Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients With Mast Cell Activation Syndrome. Cureus. 2026 Jan 22;18(1):e102064. doi: 10.7759/cureus.102064. PMID: 41728426; PMCID: PMC12924640. https://pmc.ncbi.nlm.nih.gov/articles/PMC12924640/ (Full text)

LOW VASOPRESSIN IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME

Abstract:

Objective: The complex clinical picture of ME/CFS includes orthostatic intolerance with symptoms and signs suggesting abnormal water homeostasis and hypovolemia. Since many ME/CFS patients report polyuria-polydipsia, we conducted an observational study based on series of plasma and urine osmolality (P-Osm and U-Osm) as well as plasma levels of vasopressin (P-VP) or copeptin in consecutive patients diagnosed with ME/CFS according to the International Consensus Criteria.

Methods: P-VP as well as P-Osm and U-Osm were measured in 111 patients after 10 hour overnight fasting and fluid deprivation. Additional 13 patients were assessed for copeptin, when P-VP measurements were no longer available. The clinical routine also included brain MRI and blood chemistry.

Results: P-Osm was abnormally high (>292 mOsm/kg) in 71/124 (57.3 %) and U-Osm below the reference interval (< 750 mOsm/kg) in 82/124 (66.1%) patients. P-VP was below the level of detection (<1.6 pg/mL) in 91/111 (82.0 %) patients. A normal P-VP level compared with their P-Osm was found in 11/111 (9.9 %) patients. Copeptin levels were all within the given reference range, albeit in the lower end in most patients. No indication of relevant pathology in either hypothalamus or hypophysis was present.

Conclusions: Our findings suggest that chronic down-regulation of VP mimicking central diabetes insipidus is an important measurable part of the disease mechanism that potentially contributes to criterial symptoms of ME/CFS.

Source: Huhmar HM, Soinne LS, Bertilson BC, Ghatan PH, Bragée BA, Polo OJ. LOW VASOPRESSIN IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. Endocr Pract. 2025 Dec 29:S1530-891X(25)01349-7. doi: 10.1016/j.eprac.2025.12.020. Epub ahead of print. PMID: 41475665. https://www.endocrinepractice.org/article/S1530-891X(25)01349-7/fulltext (Full text)

The Clinical Relevance of Mast Cell Activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background/Objectives: Growing evidence suggests that mast cell activation (MCA) may contribute to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating disorder characterized by persistent fatigue and post-exertional malaise (PEM). Particularly in relation to orthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (POTS), this study aimed to investigate the prevalence and clinical relevance of MCA in an Austrian ME/CFS patient cohort.

Methods: Two data sets were analyzed. The CCCFS data set, a comprehensive, patient-centered online questionnaire consisting of 687 filled surveys, focuses on patient stratification. Self-reported clinical features, disease progression, and treatment responses were analyzed. Preliminary findings were validated in a second, retrospective study, analyzing data of 383 Austrian ME/CFS patients with regard to MCA involvement and OI.

Results: Among followed-up ME/CFS patients, MCA prevalence increased over the disease course, with up to 25.3% meeting the criteria for clinically relevant MCA. ME/CFS patients with Mast Cell Activation Syndrome (MCAS) and OI reported symptom alleviation significantly more often following mast cell-targeted treatment than those without MCAS (p < 0.0001). With regard to IF-channel inhibitors, ME/CFS patients diagnosed with MCAS responded more frequently than those without MCAS (p = 0.076), while no significant differences were observed in response to beta blockers (p = 0.637). In both cohorts, OI, particularly POTS, was significantly more common in patients with MCA involvement.

Conclusions: MCA appears to be a frequent and clinically relevant comorbidity in ME/CFS and is associated with a higher prevalence of OI, particularly POTS. Stratifying patients based on MCA involvement may support personalized treatment approaches and improve clinical outcomes.

Source: Rohrhofer J, Ebner L, Schweighardt J, Stingl M, Untersmayr E. The Clinical Relevance of Mast Cell Activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Diagnostics (Basel). 2025 Nov 7;15(22):2828. doi: 10.3390/diagnostics15222828. PMID: 41300853; PMCID: PMC12651186. https://pmc.ncbi.nlm.nih.gov/articles/PMC12651186/ (Full text)

Pyridostigmine improves hand grip strength in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystemic disease characterized by exertional intolerance and fatigue which is often accompanied by muscle weakness and fatiguability. A study showed efficacy of the acetylcholinesterase inhibitor pyridostigmine on cardiac output in ME/CFS patients. Pyridostigmine is currently used off-label in ME/CFS and postural orthostatic tachycardia syndrome.

Methods: We evaluated the effect of pyridostigmine on hand grip strength in 20 patients with post-infectious ME/CFS. Hand grip strength testing was performed ten times using an electric dynamometer and was repeated after 1 h. In a second test, 30 mg of pyridostigmine was given immediately after the first measurement. Orthostatic function was assessed using a passive standing test. Neurological examination and autoantibody testing were performed to rule out a diagnosis of myasthenia gravis.

Results: All patients had reduced maximum hand grip strength with a median of 16.45 kg (IQR: 11.45 kg–22.8 kg). Hand grip strength was diminished by a median of 4.65 kg after 1 h. In contrast, 1 h after pyridostigmine administration, patients showed an improvement in maximum hand grip strength with a median increase of 2.6 kg. The maximum hand grip strength after exertion was about 1.5-fold higher with then without pyridostigmine (p = 0.01). The increase in heart rate from lying to standing was median 17 beats per minute without pyridostigmine (IQR: 13 beats per minute – 23 beats per minute) and 13 beats per minute (IQR: 9 beats per minute – 20 beats per minute) (p = 0.017) with pyridostigmine. None of the patients tested positive for myasthenia gravis specific autoantibodies.

Conclusion: Pyridostigmine exerts an immediate effect on muscle strength and orthostatic function. This may be attributed to increased acetylcholine availability at neuromuscular junctions, and its augmentation of parasympathetic tone.

Source: Schlömer Ella , Stein Elisa , Kedor Claudia , Rust Rebekka , Brock Anna , Wittke Kirsten , Scheibenbogen Carmen , Kim Laura. Pyridostigmine improves hand grip strength in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Neuroscience, Volume 19 – 2025. DOI: 10.3389/fnins.2025.1637838 ISSN: 1662-453X https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1637838/full (Full text)

Autonomic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Findings from the Multi-Site Clinical Assessment of ME/CFS (MCAM) Study in the USA

Abstract:

Background/Objectives: Symptoms of autonomic dysfunction are common in infection-associated chronic conditions and illnesses (IACCIs), including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study aimed to evaluate autonomic symptoms and their impact on ME/CFS illness severity.
Methods: Data came from a multi-site study conducted in seven ME/CFS specialty clinics during 2012–2020. Autonomic dysfunction was assessed using the Composite Autonomic Symptom Scale 31 (COMPASS-31), medical history, and a lean test originally described by the National Aeronautics and Space Administration (NASA). Illness severity was assessed using Patient-Reported Outcomes Measurement Information System measures, the 36-item short-form, as well as the CDC Symptom Inventory. This analysis included 442 participants who completed the baseline COMPASS-31 assessment, comprising 301 individuals with ME/CFS and 141 healthy controls (HC).
Results: ME/CFS participants reported higher autonomic symptom burden than HC across three assessment tools (all p < 0.0001), including the COMPASS-31 total score (34.1 vs. 6.8) and medical history indicators [dizziness or vertigo (42.6% vs. 2.8%), cold extremities (38.6% vs. 5.7%), and orthostatic intolerance (OI, 33.9% vs. 0.7%)]. Among ME/CFS participants, 97% had at least one autonomic symptom. Those with symptoms in the OI, gastrointestinal, and pupillomotor domains had significantly higher illness severity than those without these symptoms.
Conclusions: ME/CFS patients exhibit a substantial autonomic symptom burden that correlates with greater illness severity. Individualized care strategies targeting dysautonomia assessment and intervention may offer meaningful improvements in symptom management and quality of life for those with ME/CFS and similar chronic conditions.
Source: Issa A, Lin J-MS, Chen Y, Attell J, Brimmer D, Bertolli J, Natelson BH, Lapp CW, Podell RN, Kogelnik AM, et al. Autonomic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Findings from the Multi-Site Clinical Assessment of ME/CFS (MCAM) Study in the USA. Journal of Clinical Medicine. 2025; 14(17):6269. https://doi.org/10.3390/jcm14176269  https://www.mdpi.com/2077-0383/14/17/6269 (Full text)

Effects of recumbent isometric yoga on the orthostatic cardiovascular response of patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Our previous studies demonstrated that the regular practice of recumbent isometric yoga reduced the fatigue of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Some patients with ME/CFS have postural orthostatic tachycardia syndrome (POTS); however, the effects of recumbent isometric yoga on orthostatic cardiovascular responses and whether recumbent isometric yoga improves POTS remain unknown. This pilot study was done to investigate the effect of recumbent isometric yoga on the orthostatic cardiovascular response of patients with ME/CFS.

Main body: Ten adult female patients with ME/CFS performed recumbent isometric yoga for 12 weeks. Changes in their systolic blood pressure (SBP), diastolic blood pressure (DBP), and the pulse rate (PR) during an active standing test were compared before and after the 12-week regimen. Among the 10 patients, 8 manifested a normal orthostatic response and 2 manifested POTS before the yoga intervention. Patients who manifested a normal orthostatic response before yoga also manifested the normal orthostatic pattern after the yoga intervention. In contrast, the two patients who manifested POTS before the regimen showed a normal orthostatic response after completing the yoga intervention.

Conclusions: This study found that the patients who manifested POTS and performed recumbent isometric yoga for 12 weeks had a reduced increase in PR after standing up. This pilot study suggests that recumbent isometric yoga would be useful as an adjunctive nonpharmacological intervention for improving POTS in patients with ME/CFS. This finding should be confirmed in a larger number of cases.

Source: Oka T, Lkhagvasuren B. Effects of recumbent isometric yoga on the orthostatic cardiovascular response of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Biopsychosoc Med. 2025 Sep 1;19(1):16. doi: 10.1186/s13030-025-00336-w. PMID: 40890788. https://bpsmedicine.biomedcentral.com/articles/10.1186/s13030-025-00336-w (Full text)

Mapping cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance: insights from a systematic review

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating condition with a large proportion of patients that experience orthostatic intolerance (OI). This systematic review aimed to assess whether cerebral blood flow (CBF) is reduced in ME/CFS and OI, and whether the presence of both conditions leads to an additional decline in CBF.

Methods: PubMed (from 1943), MEDLINE (from 1946), EMBASE (from 1947) and Cochrane were searched from inception to February 14th, 2025, using terms including “chronic fatigue syndrome”, “myalgic encephalomyelitis”, “orthostatic intolerance” and “cerebral blood flow”. Article selection required the following criteria: published in English; CBF measured in participants with either ME/CFS or OI, or both ME/CFS and OI combined. Quality assessment and risk of bias was assessed using the Newcastle-Ottawa Scale and the systematic review was conducted in accordance with the PRISMA 2020 guidelines.

Results: Of 14,928 articles, 118 were included, 26 (22.1%) of which studied CBF in ME/CFS alone, 81 (68.6%) in OI alone and 11 (9.3%) in both ME/CFS and OI. Overall, the articles included 9185 participants, with a mean age of 39.1 years (SD = 8.8), and 73.8% of participants were female. Studies found CBF was significantly reduced in 12 of the articles focused on ME/CFS and in 56 of those focused on OI; compared to controls. Additionally, in 4 out of 11 studies that examined both conditions, CBF was further reduced in participants suffering from both conditions compared to those with ME/CFS alone.

Conclusions: CBF is reduced in ME/CFS and OI alone and having both conditions comorbidly amplifies CBF reductions. Therefore, observing CBF changes in ME/CFS with and without OI may be important in monitoring disease severity. Despite this, few studies focus on the combination of ME/CFS and OI, and OI may be a confounding factor in CBF in a large portion of ME/CFS studies.

Source: Christopoulos EM, Tantanis D, Huang K, Schneider-Futschik EK, Gooley PR, Moneghetti KJ, Armstrong CW. Mapping cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance: insights from a systematic review. J Transl Med. 2025 Aug 26;23(1):963. doi: 10.1186/s12967-025-06954-w. PMID: 40859389. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06954-w (Full text)

The Relation Between Cardiac Output and Cerebral Blood Flow in ME/CFS Patients with a POTS Response During a Tilt Test

Abstract:

Background/Objectives: Orthostatic intolerance is 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), CBF is regulated complexly, and cardiac output (CO) is an important determinant of CBF. A review in HC showed that a 30% reduction in CO results in a 10% reduction in CBF. In contrast, we showed in ME/CFS patients with a normal HR (HR) and blood pressure response during a tilt test that CO and CBF decreased to a similar extent. The relation between CO and CBF in ME/CFS patients with postural orthostatic tachycardia syndrome (POTS) is unknown.

Therefore, the aim of this study is to assess the relation between CBF and CO, in ME/CFS patients with POTS. The methods used in this retrospective study analyze this relation in a large group of patients. We also analyzed the influence of clinical data. A total of 260 ME/CFS patients with POTS underwent tilt testing with measurements of HR, BP, CBF, CO, and end-tidal PCO2. We measured CBF using extracranial Doppler flow velocity and vessel diameters obtained with a General Electric echo system, and suprasternal aortic flow velocities were measured using the same device. We recorded end-tidal PCO2 using a Nonin Lifesense device.

Results: End-tilt HR and the HR increase were significantly higher in the patients with a %CO reduction ≥ -15% than in the other group. End-tilt CO was higher and the %CO reduction was lower in patients with %CO reduction ≥ -15% than in the other group. CBF data (supine, end-tilt and the %CBF reduction) were not different between the two patient groups. The use of HR increases and %SV reductions were not as discriminative as the %CO reduction.

Conclusions: In ME/CFS patients with POTS during tilt testing with measurements of both the CO and the CBF, two different patterns were observed: (1) appr. two-thirds of patients had an almost 1:1 relation between the %CBF reduction and the %CO reduction. (2) Appr. one-third of patients showed a limited reduction in CO together with a substantial increase in HR. In these patients, there was no relation between the CO and CBF reduction. These data suggest the presence of a hyperadrenergic response.

Source: van Campen CLMC, Visser FC. The Relation Between Cardiac Output and Cerebral Blood Flow in ME/CFS Patients with a POTS Response During a Tilt Test. J Clin Med. 2025 May 22;14(11):3648. doi: 10.3390/jcm14113648. PMID: 40507411. https://www.mdpi.com/2077-0383/14/11/3648 (Full text)

Truncal ataxia or disequilibrium is an unrecognised cause of orthostatic intolerance in patients with myalgic encephalomyelitis

Introduction:

Chronic fatigue syndrome (CFS) causes a marked reduction in the activities of daily living and impairs the quality of life. Recently, dysfunction of the central nervous system associated with myalgic encephalomyelitis (ME) has been postulated as the main cause of CFS.1 Most patients with ME/CFS have orthostatic intolerance (OI) which is the primary factor restricting the daily functional capacity and in turn quality of life.2-4 OI is characterised by the inability to remain upright without severe signs and symptoms, such as hypotension, tachycardia, light-headedness, pallor, fatigue, weakness, dizziness, diminished concentration, tremulousness and nausea. Most symptoms of OI have been surmised to be related to reduced cerebral blood flow with or without impaired cerebral circulatory autoregulation, and the compensatory activation of the sympathetic nervous system.5, 6 Indeed, many patients have postural orthostatic tachycardia, delayed orthostatic hypotension and neurally mediated hypotension.4, 5, 7-9 Also many patients have low cardiac output in association with a small left ventricle.10-12 With further progression of the disease, patients may have even sitting intolerance and finally become bedridden.

Although static balance is an essential element for the performance of daily activities as well as postural stability, the possible relation between disequilibrium and OI has never been investigated. The possible role of static or truncal ataxia in the genesis of both orthostatic and sitting intolerance was examined in patients with ME.

Source: Miwa K, Inoue Y. Truncal ataxia or disequilibrium is an unrecognised cause of orthostatic intolerance in patients with myalgic encephalomyelitis. Int J Clin Pract. 2017 Jun;71(6). doi: 10.1111/ijcp.12967. PMID: 28613452. https://onlinelibrary.wiley.com/doi/10.1111/ijcp.12967 (Full text)

Awareness and Perception of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Among Pain Specialists: A Questionnaire-Based Study

Abstract:

Background: This study aims to explore the perceptions and clinical approaches of pain management specialists toward myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition characterized by persistent fatigue, widespread pain, unrefreshing sleep, and autonomic dysfunction. Given the challenges in diagnosis and management, pain specialists may play a pivotal role in symptom relief. By identifying variations in evaluation and treatment practices, this study seeks to enhance the recognition of ME/CFS and improve its clinical management within pain medicine.

Material and methods: The questionnaire was distributed in printed form to 250 pain specialists in Turkey. Given the limited number of pain physicians in the country, the study aimed to encompass all actively practicing specialists. The survey included four demographic questions, eight true-false questions, 12 multiple-choice questions, and four rating-scale questions. Data were collected anonymously. Data were analyzed using Statistical Product and Service Solutions (SPSS, version 27.0; IBM SPSS Statistics for Windows, Armonk, NY), with descriptive statistics and chi-square (χ²) tests applied to examine the relationships between awareness levels and attitudinal variables.

Results: In Turkey, 106 pain medicine physicians (42.4%) participated in the study. The average age was 40.6±8.52 years. Among the participants, 39.6% had previously heard of myalgic encephalomyelitis. Physicians were inclined to first ask the question, “Do you think you get enough sleep at night?” when evaluating these patients, with a rate of 63.2%. The majority of participants (65.9%) stated that they “occasionally” or “rarely” considered the relationship between fatigue and orthostatic intolerance. Additionally, 37.7% believed that this disease is a subtype of depression. The statement, “chronic fatigue decreases with intense aerobic exercise,” was agreed upon by 50.9% of participants. This controversial statement was particularly more common among those who were unaware of ME/CFS’s alternative name (p=0.009) and those who did not take dysautonomic disorders into account (p=0.048). When considering an ME/CFS diagnosis, physicians most frequently referred patients to the physical medicine and rehabilitation department (32.1%). Those who preferred not to refer patients to any department (12.3%) tended to find it appropriate for a patient to seek consultation at a pain medicine clinic due to widespread body pain and fatigue (χ2=11.405, p=0.044).

Conclusion: This study is the first questionnaire-based research assessing pain physicians’ awareness and attitudes toward ME/CFS. By highlighting their perspectives on its evaluation and management, our findings may improve recognition and clinical approaches to ME/CFS. Future research should focus on education and standardized guidelines to enhance patient care.

Source: Uygun GG, Gözükızıl ST, Bilen A. Awareness and Perception of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Among Pain Specialists: A Questionnaire-Based Study. Cureus. 2025 Mar 23;17(3):e81030. doi: 10.7759/cureus.81030. PMID: 40264626; PMCID: PMC12013460. https://pmc.ncbi.nlm.nih.gov/articles/PMC12013460/ (Full text)