Trial Report Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in ME/CFS, 2023, van Campen

[Dolphin]

https://www.mdpi.com/1648-9144/59/12/2153

Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
by
C. (Linda) M. C. van Campen
1,*,
Peter C. Rowe
2 and
Frans C. Visser
1


1 Stichting CardioZorg, Planetenweg 5, 2132 HN Hoofddorp, The Netherlands
2 Department of Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
*Author to whom correspondence should be addressed.
Medicina 2023, 59(12), 2153; https://doi.org/10.3390/medicina59122153
Submission received: 19 November 2023 / Revised: 6 December 2023 / Accepted: 11 December 2023 / Published: 12 December 2023

Abstract

Background and Objectives:

During tilt testing, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience an abnormal reduction in cerebral blood flow (CBF).

The relationship between this CBF reduction and symptom severity has not been examined in detail.

Our hypothesis was that ME/CFS severity is related to the degree of the CBF reduction during tilt testing.

Materials and Methods:

First, from our database, we selected ME/CFS patients who had undergone assessments of ME/CFS symptomatology and tilt tests on the same day, one at the first visit and the second during a follow-up.

The change in symptomatology was related to the change in CBF during the tilt test.

Second, we combined the data of two previously published studies (n = 219), where disease severity as defined by the 2011 international consensus criteria (ICC) was available but not published.

Results:

71 patients were retested because of worsening symptoms.

The ICC disease severity distribution (mild-moderate-severe) changed from 51/45/4% at visit-1 to 1/72/27% at follow-up (p < 0.0001).

The %CBF reduction changed from initially 19% to 31% at follow-up (p < 0.0001). Of 39 patients with stable disease, the severity distribution was similar at visit-1 (36/51/13%) and at follow-up (33/49/18%), p = ns.

The %CBF reduction remained unchanged: both 24%, p = ns. The combined data of the two previously published studies showed that patients with mild, moderate, and severe disease had %CBF reductions of 25, 29, and 33%, respectively (p < 0.0001).

Conclusions:

Disease severity and %CBF reduction during tilt testing are highly associated in ME/CFS: a more severe disease is related to a larger %CBF reduction.

The data suggest a causal relationship where a larger CBF reduction leads to worsening symptoms.


Keywords:
orthostatic intolerance; tilt-table testing; ME/CFS; stroke volume index; cardiac index; cerebral blood flow; disease severity; symptom worsening

https://twitter.com/user/status/1736015334627229704

 

[Hutan]

Nice commentary about the importance of objective measures in the introduction:

To capture and assess the severity of these complaints, several questionnaires have been developed and applied, including the Bell CFIDS disability scale, the Chalder fatigue scale, the DePaul pediatric health screening questionnaire, the DePaul post-exertional malaise questionnaire, the DePaul symptom questionnaire, and many others [3,4,5,6,7]. However, these questionnaires are subjective and there is a risk of response bias. Therefore, these questionnaires should preferably be used in conjunction with objective measures of symptoms. Examples of these objective measures are the use of heart rate (HR) changes [8,9,10], heart rate variability (HRV) differences [9,11], activity trackers [12], and peak oxygen consumption (VO2peak) or the ventilatory threshold (VO2AT) [13], biomarkers [14], hand grip strength [15], and the use of neuroimaging techniques [16]. Although some of the objective measures have been correlated to disease severity, this points to more severe symptomatology. It is not directly related to measures of symptoms. Further studies correlating symptoms to more objective measures of pathophysiology should be done.

Rationale and study hypothesis:

In recent studies, we have demonstrated that extracranial Doppler imaging of blood flow through the internal carotid arteries and the vertebral arteries during head-up tilt table testing provides an objective method of measuring changes in cerebral blood flow. These studies have confirmed that ME/CFS patients experience a statistically and clinically significant reduction in cerebral blood flow (CBF) during upright posture, with a mean reduction compared to supine values of 26%, versus just 7% in healthy adult controls [21]. This measure of CBF provides an objective assessment of one of the important physiologic abnormalities in ME/CFS. The hypothesis of the present study is that there is a relationship between the severity of the disease and the degree of CBF reduction during tilt testing.

Method:

first, we searched our database for ME/CFS patients who underwent two assessments of their ME/CFS symptomatology and who had a tilt tests on the same day as the symptom assessments, one at the first visit and the second during follow-up. The change in symptomatology was related to the change in CBF during the tilt test.

Second, we combined the data from two previously published studies of hypermobile patients (n = 200) and of long-haul COVID patients (n = 19) [22,23], where disease severity, as defined by the 2011 international consensus criteria (ICC) [1], was available.... who had undergone head-up tilt testing at the Stichting CardioZorg, an outpatient cardiology clinic specializing in the care of those with ME/CFS. ...[and] who had returned to our clinic for a re-assessment of symptoms and who underwent a second tilt test after an interval of more than 1 year.

ICC criteria
Mild - approx 50% reduction in activity
Medium - mostly housebound
Severe - mostly bed bound
Very severe - entirely bed-bound (excluded from the study as they could not undergo tilt-testing)

Heart rate, blood pressure measured - changes during tilt characterised as 'normal', 'POTS', 'orthostatic hypotension'

Internal carotid artery and vertebral artery Doppler flow velocity
Blood flow in each vessel was calculated from the mean blood flow velocities times the vessel cross-sectional area and expressed in mL/minute. Flow in the individual arteries was calculated in 3–6 cardiac cycles and data were averaged. Total CBF was calculated by adding the flow of the four arteries.

 

[forestglip]

They looked at historical records from their clinic for patients who had taken two tilt tests. They divided the records into two groups, those who had no change in symptoms at the second visit (n=39) and those who had worsened symptoms at the second visit (n=71). They looked at how much their cerebral blood flood (CBF) reduction differed between the two tests.

Though while they say that there were 71 in the worsened group in the text and Table 1, this figure that shows the group level values says n=68 without explaining why.


Looking at the following figure, no overall difference in CBF reduction in the group with unchanged symptoms. In the worsened symptom group, I only see a single participant that didn't have a greater reduction.


That's a surprisingly close relationship between worsening symptoms and greater CBF reduction. Either 68/69 or 70/71 (~98.5%) participants who reported worsening symptoms also had greater reduction.

Going back to the methods in the abstract:

Materials and Methods: First, from our database, we selected ME/CFS patients who had undergone assessments of ME/CFS symptomatology and tilt tests on the same day, one at the first visit and the second during a follow-up. The change in symptomatology was related to the change in CBF during the tilt test.

That second sentence is strange. At first read, I thought they were reporting the results of this study. But it's in the methods section. Did they select participants based on whether their change in symptoms was associated with change in CBF reduction? Even though that was the outcome of this study? That would be like picking only people who improved from a drug for a study, then reporting that the drug causes improvement in everyone.

From discussion:

Most importantly, those patients with worsening symptoms showed a significantly larger CBF reduction during repeat tilt testing, while patients with a stable symptomatology did not show a further CBF reduction. Both observations suggest that there is a strong relationship between symptom severity and CBF reduction.

 

[Snow Leopard]

That second sentence is strange. At first read, I thought they were reporting the results of this study. But it's in the methods section. Did they select participants based on whether their change in symptoms was associated with change in CBF reduction?

That is a little strange. But the method suggests that grouping was entirely due to the change in symptoms through the application of the ICC criteria. The combination of long-COVID and hypermobile patients into the ME/CFS basket was curious though.

 

[forestglip]

The combination of long-COVID and hypermobile patients into the ME/CFS basket was curious though.

That part was studied separately from the clinic health records, and it seems like they all fit ICC. They're from two previous van Campen studies on ME/CFS.

• Van Campen, C.L.M.C.; Rowe, P.C.; Visser, F.C. The myalgic encephalomyelitis/chronic fatigue syndrome patients with joint hypermobility show larger cerebral blood flow reductions during orthostatic stress testing than patients without hypermobility: A case control study. Med. Res. Arch. 2021, 9. [Google Scholar] [CrossRef]
• Van Campen, C.L.M.C.; Visser, F.C. Long-haul covid patients: Prevalence of pots are reduced but cerebral blood flow abnormalities remain abnormal with longer disease duration. Healthcare 2022, 10, 2105. [Google Scholar] [CrossRef] [PubMed]

Edit: Linked wrong study before.

 

[forestglip]

I emailed Dr. van Campen about this since I wanted to confirm if it was placed in the methods section by accident.

The change in symptomatology was related to the change in CBF during the tilt test.

She said it was on purpose, and I realized "related" can mean a technique, as well as a descriptor. So they meant:

The relationship between change in symptomatology and change in CBF was tested.

All this about CBF reduction is looking quite interesting. I wonder if any other groups have seen similar results.