Low sensitivity of abbreviated tilt table testing for diagnosing postural tachycardia syndrome in adults with ME/CFS

Low sensitivity of abbreviated tilt table testing for diagnosing postural tachycardia syndrome in adults with ME/CFS, by C (Linda) M van Campen, Peter C Rowe and Frans C Visser in Front. Pediatr., 16 November 2018

Introduction:

Orthostatic intolerance is common among individuals with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). In some ME/CFS case definitions, orthostatic intolerance is considered a core feature of the disorder.

Some studies have employed tilt table tests lasting 2-5 minutes to diagnose one common form of orthostatic intolerance, postural tachycardia syndrome (POTS). We examined the diagnostic yield of abbreviated durations of tilt testing in adults meeting criteria for ME/CFS, and identified the proportion with POTS misdiagnosed using testing of less than 10 minutes.

Methods:

Eligible participants were consecutive individuals satisfying study criteria for ME/CFS and POTS evaluated at the Stichting CardioZorg (SCZ, Hoofddorp, NL) between November 2012 and August 2018. Individuals being treated with medications commonly used to manage orthostatic intolerance were excluded. Head-up tilt table testing involved 15 minutes of supine posture then 20 minutes at 70 degrees upright. Only the data from the first 10-minutes upright were used.

POTS was defined as an increase in HR during a maximum of 10 minutes of upright tilt of at least 30 beats per minute (bpm), in the absence of either classical or delayed orthostatic hypotension. We measured the time until HR criteria for POTS were reached using survival curves, and compared survival curves between subgroups divided by age, sex, disease duration, and degree of hypocapnia during the test.

Results:

Of 627 individuals with ME/CFS evaluated during the study period, 155 met criteria for POTS. The median time to reaching HR criteria for POTS was 3 minutes. A two-minute tilt table test would miss 55% (95% CI, 48 – 63%) of those meeting POTS criteria over the course of 10 minutes upright. The median time to reaching HR criteria for POTS did not differ by sex, age, duration of ME/CFS, or hypocapnia during tilt.

Conclusions:

Abbreviated tilt table testing misses a substantial proportion of those ultimately diagnosed with POTS during a 10-minute tilt table test, and should be abandoned for the clinical diagnosis and in epidemiologic studies designed to estimate the prevalence of POTS among those with ME/CFS.

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Blood volume status in CFS/ME correlates with the presence or absence of orthostatic symptoms

Blood volume status in CFS/ME correlates with the presence or absence of orthostatic symptoms, by C (Linda) Van Campen,  Peter C Rowe and Frans C Visser in Front. Pediatr.  Oct 2018

Introduction:

Conflicting data have been published on the reduction of circulating blood volume in adults with Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). The aim of the present study was to compare blood volumes based on the presence or absence of orthostatic symptoms.

Methods and results:

12 consecutive adults with ME/CFS participated in the study. All underwent dual isotope blood volume measurement and were evaluated for a clinical suspicion of orthostatic intolerance (OI). The mean age was 34 (10) years, and median duration of disease was 7.5 (6-10) years. The mean (SD) absolute blood volume was 59 (8) ml/kg, a value -11 (7) ml/kg below the reference blood volume.

Of the 12 patients, 4 had no OI and 8 had a clinical suspicion of OI. In 8 patients with OI, absolute blood volumes were significantly lower than for the 4 without OI (56 [2] vs 66 [5]; p<0.05) as were the differences between the measured and the reference blood volume (-14 [2]; vs -4 [3]; p<0.02).

Conclusions:

Adults with ME/CFS had a significantly lower blood volume if they had a clinical suspicion of OI compared to those without a clinical suspicion of OI, as well as a significantly lower blood volume compared to the expected value. The data suggest that accounting for symptoms of OI could enhance the detection of the subset with reduced blood volume.

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A poem about Me and M.E – One stupid dot

‘What’s up TV’ presents a 2 minute poem by Stacy Hart: Me and M.E, how ‘One Stupid Dot’ makes all the difference

Stacy’s blogMama Chill…Stacy Hart…Runnin On Empty

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The development of the DePaul symptom questionnaire: original, expanded, brief & pediatric versions

The development of the DePaul symptom questionnaire: Original, expanded, brief and pediatric versions, by Leonard A Jason, Madison Sunnquist in Frontiers in Pediatrics, 6 Nov 2018

One of the key requirements of a reliable case definition is the use of standardized procedures for assessing symptoms. This article chronicles the development of the DePaul Symptom Questionnaire (DSQ) to assess symptoms of the major chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) case definitions.

The original questionnaire has been modified and expanded over time to more fully capture symptoms from various adult case definitions, and a brief as well as pediatric version have also been developed.

The DSQ has demonstrated strong psychometric properties in terms of test-retest reliability and sensitivity/specificity, as well as construct, predictive, and discriminant validity. The DSQ allows for a well-defined characterization of a patient’s illness and allows scientists and clinicians to improve diagnostic reliability when employing case
definitions of ME and CFS.

 

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CD24 expression & B cell maturation shows a novel link with energy metabolism: potential implications for patients with ME/CFS

CD24 expression and B cell maturation shows a novel link with energy metabolism: potential implications for patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome , by Fane K. Mensah, Christopher W Armstrong, Venkat Reddy, Amolak S Bansal, Saul Berkovitz, Maria Leandro and Geraldine Cambridge in Front. Immunol. 22 Oct 2018

Research abstract:

CD24 expression on pro-B cells plays a role in B cell selection and development in the bone marrow. We previously detected higher CD24 expression and frequency within IgD+ naïve and memory B cells in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) compared with age-matched healthy controls (HC). Here, we investigated the relationship between CD24 expression and B cell maturation.

In vitro stimulation of isolated B cells in response to conventional agonists were used to follow the dynamics of CD24 positivity during proliferation and differentiation (or maturation). The relationship between CD24 expression to cycles of proliferation and metabolism in purified B cells from HC was also investigated using phospho-flow (phosphorylation of AMPK-pAMPK), 1proton nuclear magnetic resonance and Mitotracker Far-red (Mitochondrial mass-MM).

In vitro, in the absence of stimulation, there was an increased percentage of CD24+ viable B cells in ME/CFS patients compared to HC (p< 0.05) following 5 days culture. Following stimulation with B cell agonists, percentage of CD24+B cells in both naïve and memory B cell populations decreased. p< 0.01). There was a negative relationship between percentage of CD24+B cells with MM (R2=0.76; p< 0.01), which was subsequently lost over sequential cycles of proliferation. There was a significant correlation between CD24 expression on B cells and the usage of glucose and secretion of lactate in vitro. Short term ligation of the B cell receptor with anti-IgM antibody significantly reduced the viability of CD24+ memory B cells compared to those cross-linked by anti-IgD or anti-IgG antibody. A clear difference was found between naïve and memory B cells with respect to CD24 expression and pAMPK, most notably a strong positive association in IgD+IgM+ memory B cells. In vitro findings confirmed dysregulation of CD24-expressing B cells from ME/CFS patients previously suggested by immunophenotype studies of B cells from peripheral blood.

CD24-negative B cells underwent productive proliferation whereas CD24+ B cells were either unresponsive or susceptible to cell death upon BCR-engagement alone. We suggest that CD24 expression may reflect variations in energy metabolism on different B cell subsets.

Cort Johnson discusses this research on the Simmaron Research blog: Immune Study Adds to Evidence Of Body-Wide Problems With Energy Production in Chronic Fatigue Syndrome (ME/CFS)

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Workwell’s two-day exercise tests & breaking the deconditioning dilemma in ME/CFS

Workwell’s two-day exercise tests and breaking the deconditioning dilemma in Chronic Fatigue Syndrome (ME/CFS) by Cort Johnson in Health rising blog, 19 Nov 2018

The first word in the first sentence of the paper says it all:

“Concise methodological directions for administration of serial cardiopulmonary exercise testing (CPET) are needed for testing of patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).”

Why concise? Because Workwell asserts that in the universe of diseases known to man Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is so different when it comes to exercise that it needs a place all it’s own. It needs it’s own concise methodology, and above all it needs to be understood differently.

This methodology paper, then, is an attempt by the exercise physiologists at Workwell (Staci Stevens, Mark Van Ness, Chris Snell, Jared Stevens) and Betsy Keller to spread the word that something very different, something perhaps even unique in the annals of medicine, is occurring in people with chronic fatigue syndrome when they exercise.

Someone, it seems, is listening. This dry, seemingly obscure methodology paper (“Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome“) has proven to be a surprise hit. In the two months since its publication it’s been viewed by over 7400 people spread across the globe…

It’s a remarkable fact that even people with disabling diseases can exercise to exhaustion two days in a row without effecting their ability to produce energy

Workwell has been giving two-day CPETs for years. I asked Staci if the drop in energy production seen in an exercise test given one day after a previous test was really unique in ME/CFS. Her answer demonstrated just how much we have to learn:

Clinically we have seen patients with more than 30 different fatiguing conditions including POTS and fibromyalgia. ME/CFS is unique but more research is needed to determine ME/CFS CPET subsets and if other conditions have abnormal test 2 responses.

Our clinical patients often have comorbid conditions, so this makes it more difficult to sort out. That said, several distinct subsets of abnormal responses are emerging. We have a case series on this very topic comparing fatiguing conditions with ME/CFS which will be published soon.

Read more about:

  • POTS & deconditioning
  • Workwell’s plans for larger exercise tests
  • A Guide to Giving a Two-Day Exercise Test in ME/CFS – The Methodology Section
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Associations between clinical symptoms, plasma norepinephrine & deregulated immune gene networks in subgroups of adolescents with CFS

Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome, by Chinh Bkrong Nguyen, Surendra Kumar, Manuela Zucknick, Vessela N Kristensen, Johannes Gjerstad, Hilde Nilsen, Vegard BruunWyller, in Brain Behav Immun. 2018 Nov 9. pii: S0889-1591(18)30796-7 [Epub ahead of print]

Highlights:

Research abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology.

METHODS: We analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls). Deconvolution of immune cell subtypes based on gene expression profile was performed using CIBERSORT. Supervised consensus clustering on pathway deregulation score (PDS) was used to define CFS subgroups. Associations between PDS and immune, neuroendocrine/autonomic and clinical markers were examined. The impact of plasma norepinephrine level on clinical markers over time was assessed in a larger cohort (91 patients).

RESULTS: A group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS. Group 1P (high PDS, low norepinephrine, low naïve CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naïve CD4+composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score.

CONCLUSION: We identified 29 immune-gene sets linked to plasma norepinephrine level that could delineate CFS subgroups. Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue. Our data suggests potential involvement of neuro-immune dysregulation and genetic stratification in CFS.

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The abnormal cardiac index & stroke volume index changes during a normal tilt table test in ME/CFS patients… are not related to deconditioning

The abnormal cardiac index and stroke volume index changes during a normal tilt table test in ME/CFS patients compared to healthy volunteers, are not related to deconditioning, by C (Linda) MC van Campen, Frans C. Visser in Journal of Thrombosis and Circulation, 7 November, 2018

Research abstract: 

1.1    Background. A small study in ME/CFS (Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome) patients undergoing tilt testing, showed that, despite a normal tilt test, stroke volumes and cardiac output were lower than in healthy volunteers. Moreover, it was suggested that this difference was related to deconditioning of patients.

Aim of the study. We performed table testing in 150 ME/CFS patients. Stroke volumes and cardiac output were related to the severity of the disease.

1.2    Methods and results. In the patients the severity of the disease was clinically evaluated according to the ME criteria and scored as mild, moderate or severe disease. In a subgroup of 109 patients this clinical diagnosis was confirmed by the physical functioning score of the Rand-36 questionnaire. Significantly lower physical functioning scores (indicating worse functioning) were observed in the more severely affected patients. Stroke Volume Index (SVI) and Cardiac Index (CI) were measured by suprasternal aortic Doppler imaging in the supine position, prior to the tilt, and twice during the tilt. Thirty-seven healthy volunteers underwent the same tilt protocol. In all patients and all healthy volunteers, a normal heart rate and blood pressure response was observed during the tilt. The decreases in SVI and CI during the tilt was significantly larger in patients compared to the SVI and CI decrease in HV. The decrease in SVI and CI were similar and not significantly different between the mild, moderate, and severe ME groups.

1.3    Conclusions. During a normal tilt table test decreases in SVI and CI decrease are significantly greater in ME/CFS patients than in HV, consistent with previous work. The absence of differences between patients with mild, moderate, and severe ME/CFS suggests that the decreases in stroke volumes and cardiac output are not related to deconditioning. Other factors like decreased blood volumes and autonomic dysfunction may cause this difference in the hemodynamic response between ME/CFS patients and HV.

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Low omega-3 index & polyunsaturated fatty acid status in patients with CFS/ME

Low omega-3 index and polyunsaturated fatty acid status in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, by Jesús Castro-Marrero, Joan Carles Domingo, Alba Martinez-Martinez, José Alegre, Clemens von Schacky in Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA) [Published online: November 9, 2018]

Highlights:

  • Erythrocyte omega-3 index (5.75%) and n-3 PUFA levels are low in individuals with CFS/ME.
  • The erythrocyte omega-3 index may be a useful biomarker of overall health, but cut-off points need be validated in the Spanish CFS/ME population.
  • This study suggests that low EPA + DHA levels may be a risk factor for poor cardiovascular health and pro-inflammatory status in CFS/ME. Understanding the role of omega-3 PUFAs and immunometabolism should be the next step.
  • Further studies of omega-3 fatty acid supplementation in CFS/ME are warranted.

Research abstract:

Background:
Several studies have suggested that low levels of omega-3 fatty acids (n-3 PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with cardiovascular risk, major depression, sleep problems, inflammation and other health-related issues. So far, however, erythrocyte PUFA status in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) has not been established. This study aimed to determine whether n-3 PUFA content and omega-3 index are associated with measures in CFS/ME patients.

Patients and Methods:
PUFA levels and omega-3 index were measured in 31 Spanish CFS/ME patients using the HS-Omega-3 Index® method. Demographic and clinical characteristics and self-reported outcome measures were also recorded.

Results:
A low mean omega-3 index (5.75%) was observed in 92.6% of the sample. Omega-3 index was inversely correlated with the AA/EPA ratio (p= 0.00002) and the BMI (p= 0.0106). In contrast, the AA/EPA ratio was positively associated with the BMI (p= 0.0038). No association for FIS-40 and PSQI measures was found (p> 0.05).

Conclusion:
The low omega-3 index found in our CFS/ME patients may indicate increased risks for cardiovascular health, which should be further investigated. A low omega-3 index also suggests a pro-inflammatory state in these patients. Attempts should be made to increase the omega-3 index in CFS/ME patients, based on intervention trials assessing a potential therapeutic value.

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