Category: Symptoms

Fatigue in ANCA-associated vasculitis (AAV) and systemic sclerosis (SSc): similarities with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A critical review of the literature

Abstract:

Introduction: Persistent debilitating fatigue is a frequent complaint in patients with systemic autoimmune rheumatic diseases (SARDs). Fatigue is, however, frequently overlooked in the clinic, and patients who successfully achieve remission of their disease, often still have a lowered quality of life due to its persistence. How similar is this fatigue to Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), what is this fatigue associated with, and what tools/approaches (if any), have resulted in the improvement of fatigue in these patients is poorly defined.

Areas covered: Similarities between the pathophysiology of ME/CFS, systemic sclerosis (SSc) and primary systemic vasculitides (PSV) are discussed, followed by an in-depth review of the prevalence and correlates of fatigue in these diseases. The authors reviewed literature from MEDLINE, APA PsycInfo, Embase, and CINAHL.

Expert opinion: Persistent fatigue is a prominent feature in SARDs and may not be associated with components commonly associated with disease activity and/or progression. Immune and metabolic commonalities exist between ME/CFS, SSc, and PSVs – suggesting that common pathways inherent to the diseases and fatigue may be present. We suggest that patients with features of ME/CFS need to be identified by treating physicians, as they may require alternative approaches to therapy to improve their quality of life.

Source: van Eeden C, Osman MS, Cohen Tervaert JW. Fatigue in ANCA-associated vasculitis (AAV) and systemic sclerosis (SSc): similarities with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A critical review of the literature. Expert Rev Clin Immunol. 2022 Aug 31:1-22. doi: 10.1080/1744666X.2022.2116002. Epub ahead of print. PMID: 36045606. https://pubmed.ncbi.nlm.nih.gov/36045606/

Functional Vitamin B12 deficiency in Chronic Fatigue Syndrome

Abstract:

Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) is a complex chronic condition, characterized by periods of extreme fatigue, for which an underlying medical condition has previously not been identified.

Many of the symptoms of CFS/ME, are, though, similar to those with vitamin B12 deficiency. In contrast to nutritional vitamin B12 deficiency, the majority of individuals with CFS have been shown to have functional vitamin B12 deficiency as well as functional vitamin B2 deficiency.

This functional B12 deficiency occurred despite elevated serum B12 being found, and hence presents as Paradoxical vitamin B12 deficiency. As such, CFS due to functional B2 deficiency presents as Paradoxical B12 deficiency.

Maintenance of vitamin B12 functional activity is critically dependent upon functional B2 sufficiency, and hence resolution of CFS there must first be resolution of functional B2 deficiency before treatment with vitamin B12 can be effective.

Disclosures: Gregory Russell-Jones is the director of B12 Oils Pty Ltd, a company that specializes in the manufacture and supply of vitamin B12 Oils.

Source: Gregory Russell-Jones.(2022). Functional Vitamin B12 deficiency in Chronic Fatigue Syndrome. Int J Psychiatry 7(3): 153-158. https://www.researchgate.net/publication/362644480_Functional_Vitamin_B12_deficiency_in_Chronic_Fatigue_Syndrome_International_Journal_of_Psychiatry_Corresponding_author (Full text available as PDF file)

Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice

Abstract:

The gut microbiota has been implicated in chronic pain disorders, including irritable bowel syndrome (IBS), yet specific pathophysiological mechanisms remain unclear. We showed that decreasing intake of fermentable carbohydrates improved abdominal pain in patients with IBS, and this was accompanied by changes in the gut microbiota and decreased urinary histamine concentrations.

Here, we used germ-free mice colonized with fecal microbiota from patients with IBS to investigate the role of gut bacteria and the neuroactive mediator histamine in visceral hypersensitivity. Germ-free mice colonized with the fecal microbiota of patients with IBS who had high but not low urinary histamine developed visceral hyperalgesia and mast cell activation. When these mice were fed a diet with reduced fermentable carbohydrates, the animals showed a decrease in visceral hypersensitivity and mast cell accumulation in the colon. We observed that the fecal microbiota from patients with IBS with high but not low urinary histamine produced large amounts of histamine in vitro.

We identified Klebsiella aerogenes, carrying a histidine decarboxylase gene variant, as a major producer of this histamine. This bacterial strain was highly abundant in the fecal microbiota of three independent cohorts of patients with IBS compared with healthy individuals. Pharmacological blockade of the histamine 4 receptor in vivo inhibited visceral hypersensitivity and decreased mast cell accumulation in the colon of germ-free mice colonized with the high histamine-producing IBS fecal microbiota. These results suggest that therapeutic strategies directed against bacterial histamine could help treat visceral hyperalgesia in a subset of patients with IBS with chronic abdominal pain.

Source: De Palma G, Shimbori C, Reed DE, Yu Y, Rabbia V, Lu J, Jimenez-Vargas N, Sessenwein J, Lopez-Lopez C, Pigrau M, Jaramillo-Polanco J, Zhang Y, Baerg L, Manzar A, Pujo J, Bai X, Pinto-Sanchez MI, Caminero A, Madsen K, Surette MG, Beyak M, Lomax AE, Verdu EF, Collins SM, Vanner SJ, Bercik P. Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice. Sci Transl Med. 2022 Jul 27;14(655):eabj1895. doi: 10.1126/scitranslmed.abj1895. Epub 2022 Jul 27. PMID: 35895832. https://pubmed.ncbi.nlm.nih.gov/35895832/

Histamine-producing gut bacteria can trigger chronic abdominal pain

Press Release: Hamilton, ON (July 27, 2022) – Researchers from McMaster University and Queen’s University have discovered a gut bacterial ‘super-producer’ of histamine that can cause pain flare-ups in some patients with irritable bowel syndrome (IBS).

The culprit is what has now been named Klebsiella aerogenes, the McMaster-Queen (MQ) strain, identified in up to 25 per cent of gut microbiota samples from patients with IBS. Researchers examined stool microbiota samples from both Canadian and American patient cohorts.

“We followed up these patients for several months and found high levels of stool histamine at the time when the patients reported severe pain, and low stool histamine when they were pain-free,” said senior author Premysl Bercik, professor of medicine of McMaster’s Michael G. DeGroote School of Medicine and a gastroenterologist.

The McMaster-Queen’s research team pinpointed the bacterium Klebsiella aerogenes as the key histamine producer by studying germ-free mice colonized with gut microbiota from patients with IBS. They also colonized some mice with gut microbiota from healthy volunteers as a control group.

The study found that the bacterium Klebsiella aerogenes converts dietary histidine, an essential amino acid present in animal and plant protein, into histamine, a known mediator of pain.

The bacterial histamine then activates the gut immune system through histamine-4 receptor, which draws immune mast cells into the intestines. These activated mast cells produce even more histamine and other pain-signalling mediators, triggering inflammation and pain.

“Now that we know how the histamine is produced in the gut, we can identify and develop therapies that target the histamine producing bacteria,” said first author Giada de Palma, assistant professor of medicine at McMaster.

The study found that when the mice colonized with histamine producing bacteria were fed a diet low in fermentable carbohydrates, bacterial histamine production dramatically decreased. This was due to change in bacterial fermentation and acidity within the gut, which inhibited the bacterial enzyme responsible for histamine production.

Bercik said that these results explain the beneficial effects of a low fermentable diet observed in patients with IBS.

It is known that patients with IBS have more mast cells in their intestines, and that some of them improve with treatments targeting mast cells or histamine, such as mast cell stabilizers or antihistamines.

“Although mast cell treatment in IBS has been explored, a novel approach based on our research would be targeting the bacterial histamine production or H4R pathways,” Bercik said.

The McMaster-Queen’s study explains why increased mast cells are found in IBS and suggests that H4 receptor pathway plays a major role in this process.

“If we block the H4 receptors, then we can prevent recruitment of mast cells to the colon and subsequently the development of abdominal pain,” said senior co-author Stephen Vanner, professor of medicine at Queen’s University.

“Many but not all IBS patients will benefit from therapies targeting this histamine driven pathway,” said co-first author David Reed, assistant professor of medicine at Queen’s. Reed said that one or more biomarkers of this pathway could be used to find the patients most likely to benefit.

The McMaster-Queens study was funded by the Canadian Institutes of Health Research.

The study was published in the journal Science Translational Medicine on July 27.

Click HERE to read the study.

 

Orthostatic intolerance as a potential contributor to prolonged fatigue and inconsistent performance in elite swimmers

Abstract:

Background: Athletic underperformance is characterized by fatigue and an inability to sustain a consistent exercise workload. We describe five elite swimmers with prolonged fatigue and athletic underperformance. Based on our work in myalgic encephalomyelitis /chronic fatigue syndrome, we focused on orthostatic intolerance as a possible contributor to symptoms.

Methods: Participants were referred for evaluation of fatigue and underperformance to the Chronic Fatigue Clinic at the Johns Hopkins Children’s Center. All patients were evaluated for overtraining syndrome, as well as for features commonly seen in myalgic encephalomyelitis/chronic fatigue syndrome. The latter included joint hypermobility, orthostatic intolerance, and non-IgE mediated milk protein intolerance. Orthostatic intolerance was tested by performing a ten-minute passive standing test or a head-up tilt table test.

Results: Orthostatic testing provoked fatigue and other symptoms in all five swimmers, two of whom met heart rate criteria for postural tachycardia syndrome. Treatment was individualized, primarily consisting of an increased intake of sodium chloride and fluids to address orthostasis. All patients experienced a relatively prompt improvement in fatigue and other orthostatic symptoms and were able to either return to their expected level of performance or improve their practice consistency.

Conclusions: Orthostatic intolerance was an easily measured and treatable contributor to athletic underperformance in the five elite swimmers we describe. We suggest that passive standing tests or formal tilt table tests be incorporated into the clinical evaluation of athletes with fatigue and underperformance as well as into scientific studies of this topic. Recognition and treatment of orthostatic intolerance provides a new avenue for improving outcomes in underperforming athletes.

Source: Petracek LS, Eastin EF, Rowe IR, Rowe PC. Orthostatic intolerance as a potential contributor to prolonged fatigue and inconsistent performance in elite swimmers. BMC Sports Sci Med Rehabil. 2022 Jul 23;14(1):139. doi: 10.1186/s13102-022-00529-8. PMID: 35870963. https://bmcsportsscimedrehabil.biomedcentral.com/articles/10.1186/s13102-022-00529-8 (Full text)

The higher resting heart rate in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients compared to healthy controls: relation with stroke volumes

Abstract:

Introduction: In patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) a higher-than-normal resting heart rate has been reported in a number of studies. As heart rate is linked to stroke volume, the present study explored the relationship between the supine heart rate and stroke volume index in healthy controls and in ME/CFS patients. Moreover, as patients with a postural orthostatic tachycardia syndrome (POTS) during tilt testing, have a higher supine heart rate than patients with a normal heart rate and blood pressure response during tilting, these two patient groups were also compared.

Methods and results: From a database of individuals who had undergone tilt-testing, including supine Doppler measurements for stroke volume index calculation, we selected ME/CFS patients and healthy controls without evidence of hypotension or syncope. 474 ME/CFS patients were analyzed, 314 with a normal heart rate and blood pressure response and 160 with POTS during tilt-testing, and 56 healthy controls. Resting stroke volume indices were similar between the 3 groups. All 3 groups had an inverse relation between the resting stroke volume index and resting heart rate (all p<0.0001). The slope of the relation was not significantly different between the 3 groups. Using the upper limit of the 95% prediction interval for the heart rate of healthy controls, 46 (15%) of patients with a normal heart rate and blood pressure response had a resting heart rate above the upper limit, 248 (85%) a heart rate between the upper and lower limit. In 47 (29%) patients developing POTS the resting heart rate was above the upper limit, and in 113 (71%) patients within the upper limit and lower limit. This distribution was significantly different between the two patient groups (p=0.0001).

Conclusion: Patients and healthy controls showed a significant and inverse relation between the SVI and heart rate at rest. Already at rest heart rate in patients developing POTS during tilt-testing were higher compared to the patients with a normal heart rate and blood pressure response per unit of SVI, but the heart rate of the majority of all patients fell within the limits of normal of healthy controls. The difference of patients with heart rate above the upper limit versus between the upper limit and lower limit deserves further investigation and may have therapeutic implications.

Source: VAN CAMPEN, C (Linda) M.C.; VISSER, Frans C.. The higher resting heart rate in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients compared to healthy controls: relation with stroke volumes.. Medical Research Archives, [S.l.], v. 10, n. 6, june 2022. ISSN 2375-1924. Available at: https://esmed.org/MRA/mra/article/view/2891. Date accessed: 17 july 2022. doi: https://doi.org/10.18103/mra.v10i6.2891.

Comparison of the Degree of Deconditioning in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients with and without Orthostatic Intolerance

Abstract:

Background: Orthostatic intolerance (OI) is a core finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Deconditioning is often proposed as an important determinant for OI. Deconditioning can be objectively classified using the predicted peak oxygen consumption (%VO2 peak) values as derived from cardiopulmonary exercise testing (CPET) and OI can be objectively quantified using cerebral blood flow (CBF) changes during tilt testing. Therefore, if deconditioning contributes to OI, a correlation between peak VO2 and the %CBF reduction is expected.

Methods and results: 18 healthy controls (HC) and 122 ME/CFS patients without hypotension or tachycardia on tilt testing were studied. Deconditioning was classified as follows: %VO2 peak ≥85%= no deconditioning, %VO2 peak 65-85%= mild deconditioning, %VO2 peak<65%= severe deconditioning. HC had higher %VO2 peak compared to ME/CFS patients (p<0.0001). ME/CFS patients had significantly larger CBF reduction than HC (p<0.0001). No relation between the degree of deconditioning by the %VO2 peak and the %CBF reduction in ME/CFS patients was found. Moreover, we separately analyzed ME/CFS patients without an abnormal CBF reduction. Despite equal CBF reductions compared to HC and large differences between these patients and the patients with an abnormal CBF reduction, cardiac index (CI) changes (measured by suprasternal Doppler) were significantly less compared to ME/CFS patients with an abnormal CBF reduction (p<0.0001) but larger than in HC (p=0.004). Despite these different hemodynamic findings, %VO2 values were not different between the two patient groups, argumenting again against the causative role of hemodynamic abnormalities in deconditioning.

Conclusion: In ME/CFS patients without hypotension or tachycardia there is no relation between the %VO2 peak during CPET and the %CBF and %CI reduction during tilt testing, whether or not patients have an abnormal CBF reduction during tilt testing. It suggests again that deconditioning does not play an important role in OI.

Source: VAN CAMPEN, C (Linda) M.C.; VISSER, Frans C.. Comparison of the Degree of Deconditioning in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients with and without Orthostatic Intolerance. Medical Research Archives, [S.l.], v. 10, n. 6, june 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2858>. Date accessed: 17 july 2022. doi: https://doi.org/10.18103/mra.v10i6.2858.

Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID

Abstract:

Background and Objectives: COVID-19 can be serious not only in the acute phase but also after the acute phase and some patients develop ME/CFS. There have been few studies on patients with long COVID in whom ME/CFS was diagnosed by physicians based on standardized criteria after examinations and exclusion diagnosis and not based on only subjective symptoms. The purpose of this study was to elucidate the detailed characteristics of ME/CFS in patients with long COVID.
Materials and Methods: A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period was from February 2021 to April 2022.
Results: Clinical data were obtained from medical records for 281 patients, and 279 patients who met the definition of long COVID were included. The overall prevalence rate of ME/CFS diagnosed by three sets of ME/CFS criteria (Fukuda, Canadian and IOM criteria) was 16.8% (48.9% in male and 51.1% in females). The most frequent symptoms in ME/CFS patients were general fatigue and post-exertional malaise (89.4% of the patients), headache (34.0%), insomnia (23.4%), dysosmia (21.3%) and dysgeusia (19.1%). Dizziness, chest pain, insomnia and headache were characteristic symptoms related to ME/CFS. The male to female ratio in ME/CFS patients was equal in the present study, although ME/CFS was generally more common in women in previous studies. Given that patients with ME/CFS had more severe conditions in the acute phase of COVID-19, the severity of the acute infectious state might be involved in the pathophysiology of ME/CFS.
Conclusions: The prevalence rate of ME/CFS and the characteristic sequelae in the long COVID condition were revealed in this study.
Source: Tokumasu K, Honda H, Sunada N, Sakurada Y, Matsuda Y, Yamamoto K, Nakano Y, Hasegawa T, Yamamoto Y, Otsuka Y, Hagiya H, Kataoka H, Ueda K, Otsuka F. Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID. Medicina. 2022; 58(7):850. https://doi.org/10.3390/medicina58070850 https://www.mdpi.com/1648-9144/58/7/850/htm (Full text)

An online survey of pelvic congestion support group members regarding comorbid symptoms and syndromes

Abstract:

Objectives: Patients with pelvic congestion syndrome (PCS) often report overlapping somatic symptoms and syndromes. The objective of this study was to explore the prevalence of co-existing symptoms and self-reported syndrome diagnoses among women with PCS and to inform future research hypotheses.

Methods: A brief online survey was offered to members of a PCS support group website. Responses were assessed for self-reported co-existing symptoms and formal diagnoses, including: chronic fatigue syndrome, fibromyalgia, postural tachycardia syndrome, irritable bowel syndrome, migraines, interstitial cystitis, and temporomandibular joint dysfunction.

Results: Of a total of 6000 members, there were 398 respondents; 232 (59%) had not yet been treated for PCS. Among these, the most prevalent co-existing symptoms were as follows: severe fatigue (72%), dizziness (63%), IBS symptoms (61%), brain fog (33%), migraines (49%), polyuria or dysuria (41%), excessive sweating (31%), TMJ pain (31%), and loose skin or lax joints (18%). These are much higher than reported for the general female population. The most commonly self-reported comorbid syndrome diagnoses for the overall group of 398 were: irritable bowel syndrome (29%), fibromyalgia (13%), spinal nerve problems (18%), interstitial cystitis (10%), postural tachycardia syndrome (9%), hypertension (11%), chronic fatigue syndrome (10%), and Ehlers-Danlos syndrome (6%). Other than with hypertension, these rates are variably higher than in the general population.

Conclusion: Several self-reported co-existing symptoms and syndromes are more prevalent in members of a PCS support group relative to the reported prevalence in the general population. More formal investigation is warranted to evaluate this finding and to investigate potential etiologic links. Ehlers-Danlos Syndrome appears to be common in self identifying PCS women.

Source: Smith SJ, Sichlau M, Sewall LE, Smith BH, Chen B, Khurana N, Rowe PC. An online survey of pelvic congestion support group members regarding comorbid symptoms and syndromes. Phlebology. 2022 Jul 13:2683555221112567. doi: 10.1177/02683555221112567. Epub ahead of print. PMID: 35831253. https://pubmed.ncbi.nlm.nih.gov/35831253/

Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain

Abstract:

The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking.

Here, we discovered that in the Freund’s adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans.

As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.

Source: Dedek A, Xu J, Lorenzo LÉ, Godin AG, Kandegedara CM, Glavina G, Landrigan JA, Lombroso PJ, De Koninck Y, Tsai EC, Hildebrand ME. Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain. Brain. 2022 Apr 29;145(3):1124-1138. doi: 10.1093/brain/awab408. PMID: 35323848; PMCID: PMC9050559. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050559/ (Full text)