Psychogenic Pseudosyncope: Real or Imaginary? Results from a Case-Control Study in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients

Background and objectives: Orthostatic intolerance (OI) is a clinical condition in which symptoms worsen upon assuming and maintaining upright posture and are ameliorated by recumbency. OI has a high prevalence in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Exact numbers on syncopal spells especially if they are on a weekly or even daily basis are not described. Although not a frequent phenomenon, this symptomatology is of very high burden to the patient if present. To explore whether patients with very frequent (pre)syncope spells diagnosed elsewhere with conversion or psychogenic pseudosyncope (PPS) might have another explanation of their fainting spells than behavioral psychiatric disorders, we performed a case–control study comparing ME/CFS patients with and without PPS spells. Methods and results: We performed a case–control study in 30 ME/CFS patients diagnosed elsewhere with PPS and compared them with 30 control ME/CFS patients without syncopal spells. Cases were gender, age and ME/CFS disease duration matched. Each underwent a tilt test with extracranial Doppler measurements for cerebral blood flow (CBF). ME/CFS cases with PPS had a significant larger CBF reduction at end tilt than controls: 39 (6)% vs. 25 (4)%; (p < 0.0001). Cases had more severe disease compared with controls (chi-square p < 0.01 and had a p = 0.01) for more postural orthostatic tachycardia syndrome in cases compared with controls. PETCO2 end-tilt differed also, but the magnitude of difference was smaller than compared with the CBF reduction: there were no differences in heart rate and blood pressure at either end-tilt testing period. Compared with the test with the stockings off, the mean percentage reduction in cardiac output during the test with compression stockings on was lower, 25 (5) mmHg versus 29 (4) mmHg (p < 0.005). Conclusions: This study demonstrates that in ME/CFS patients suspected of having PPS, or conversion, CBF measurements end-tilt show a large decline compared with a control group of ME/CFS patients. Therefore, hypoperfusion offers an explanation of the orthostatic intolerance and syncopal spells in these patients, where it is clear that origin might not be behavioral or psychogenic, but have a clear somatic pathophysiologic background.

Differential Effects of Exercise on fMRI of the Midbrain Ascending Arousal Network Nuclei in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) in a Model of Postexertional Malaise (PEM)

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and control subjects underwent fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020). Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction. Methods: Activated midbrain nuclei were inferred by a re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network. Results: Before exercise, control and GWI subjects showed greater activation during cognition than ME/CFS in the left pedunculotegmental nucleus. Post exercise, ME/CFS subjects showed greater activation than GWI ones for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI, indicating reciprocal patterns of activation. The controls had no changes. Conclusions: Exercise caused the opposite effects with increased activation in ME/CFS but decreased activation in GWI, indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI.

New guidance for ME and CFS to improve understanding of these largely misunderstood conditions

The National Institute for Health and Care Excellence has published new guidelines on myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Sarah Jane Palmer looks at the key changes made

Male vs. Female Differences in Responding to Oxygen–Ozone Autohemotherapy (O2-O3-AHT) in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

(1) Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a syndrome that has fatigue as its major symptom. Evidence suggests that ozone is able to relieve ME/CFS-related fatigue in affected patients. (2) Objective: To evaluate whether differences exist between males and females in ozone therapy outputs in ME/CFS. (3) Methods: In total, 200 patients previously diagnosed with ME/CFS (mean age 33 ± 13 SD years) underwent treatment with oxygen–ozone autohemotherapy (O2-O3-AHT). Fatigue was investigated via an FSS 7-scoring questionnaire before and following 1 month after treatment. (4) Results: The Mann-Whitney test (MW test) assessed the significance of this difference (H = 13.8041, p = 0.0002), and female patients showed better outcomes than males. This difference was particularly striking in the youngest age cohort (14–29 years), and a KW test resulted in H = 7.1609, p = 0.007 for the Δ = 28.3% (males = 3.8, females = 5.3). (5) Conclusions: When treated with O2-O3-AHT, females respond better than males.

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Greatly Improved Fatigue Symptoms When Treated with Oxygen-Ozone Autohemotherapy

(1) Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic syndrome characterized by fatigue as its major and most outstanding symptom. Previous evidence has supported the ability of ozone to relief ME/CFS related fatigue in affected patients (2) Methods: A number of 200 ME/CFS previously diagnosed patients, (mean age 33 ± 13 SD years) were consecutively treated with oxygen-ozone autohemotherapy (O2-O3-AHT). Fatigue was evaluated via an FSS 7-scoring questionnaire before and following 30 days after treatment. (3) Results: Almost half (43.5%) of the treated patients evolved their FSS scale from the worst (7) to the best (1) score, assessing the highest improvement from being treated with O2-O3-AHT. Furthermore 77.5% of patients experienced significant ameliorations of fatigue, of 4–6 delta score. No patient showed side effects, yet experienced long lasting fatigue disappearance, by three months follow up (4) Conclusions: Treatment with O2-O3-AHT greatly improves ME/CFS related fatigue, aside from sex and age distribution.

A Cartography of Differential Gene Methylation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Different Network Roles in the Protein-Protein Interactions Network Play Different, Biologically Relevant, Roles

Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a debilitating illness characterised by severe fatigue and associated with immune dysfunction. Previous studies of DNA methylation (epigenetic changes that can affect the gene transcription) have found evidence of changes in immune cells for ME/CFS. However these studies have been limited by their small sample size, precluding the ability to detect changes to methylation of smaller magnitude. Therefore, to achieve a larger sample size and detect small changes to DNA methylation, we aggregate three comparable datasets and analyse them in unison. We find 10,824 differentially methylated genes, with a very small average change. We then turn our attention to the network structure of the Protein-Protein interaction, which we built from the currently known interactions of relevant proteins, and localising the network cartography framework, we identify 184 hub genes. A distinct structuring emerges, with different hub types playing differing, meaningful, biological roles. Supporting previous theories about ME/CFS, Gene ontology enrichment analysis of these hubs reveal that they are involved in immune system processes, including response to TGF-β and LPS, as well as mitochondrial functioning. We also show that dopaminergic signalling may potentially contribute to immune pathology in ME/CFS. Our results demonstrate the potentiality of network cartographic approaches in shedding light on the epigenetic contribution to the immune dysregulation of ME/CFS.

Brainstem Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem medical condition with heterogeneous symptom expression. Currently, there is no effective cure or treatment for the standard care of patients. A variety of ME/CFS symptoms can be linked to the vital life functions of the brainstem, the lower extension of the brain best known as the hub relaying information back and forth between the cerebral cortex and various parts of the body.Objective/Methods: Over the past decade, Magnetic Resonance Imaging (MRI) studies have emerged to understand ME/CFS with interesting findings, but there has lacked a synthesized evaluation of what has been found thus far regarding the involvement of the brainstem. We conducted this study to review and evaluate the recent MRI findings via a literature search of the MEDLINE database, from which 11 studies met the eligibility criteria.Findings: Data showed that MRI studies frequently reported structural changes in the white and gray matter. Abnormalities of the functional connectivity within the brainstem and with other brain regions have also been found. The studies have suggested possible mechanisms including astrocyte dysfunction, cerebral perfusion impairment, impaired nerve conduction, and neuroinflammation involving the brainstem, which may at least partially explain a substantial portion of the ME/CFS symptoms and their heterogeneous presentations in individual patients.Conclusions: This review draws research attention to the role of the brainstem in ME/CFS, helping enlighten future work to uncover the pathologies and mechanisms of this complex medical condition, for improved management and patient care.

Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue and postexertional malaise. We developed a provocation paradigm with two submaximal bicycle exercise stress tests on consecutive days bracketed by magnetic resonance imaging, orthostatic intolerance, and symptom assessments before and after exercise in order to induce objective changes of exercise induced symptom exacerbation and cognitive dysfunction.Method: Blood oxygenation level dependent (BOLD) scans were performed while at rest on the preexercise and postexercise days in 34 ME/CFS and 24 control subjects. Seed regions from the FSL data library with significant BOLD signals were nodes that clustered into networks using independent component analysis. Differences in signal amplitudes between groups on pre- and post-exercise days were determined by general linear model and ANOVA.Results: The most striking exercise-induced effect in ME/CFS was the increased spontaneous activity in the medial prefrontal cortex that is the anterior node of the Default Mode Network (DMN). In contrast, this region had decreased activation for controls. Overall, controls had higher BOLD signals suggesting reduced global cerebral blood flow in ME/CFS.Conclusion: The dynamic increase in activation of the anterior DMN node after exercise may be a biomarker of postexertional malaise and symptom exacerbation in CFS. The specificity of this postexertional finding in ME/CFS can now be assessed by comparison to post-COVID fatigue, Gulf War Illness, fibromyalgia, chronic idiopathic fatigue, and fatigue in systemic medical and psychiatric diseases.