Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

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

Figure 1

Flow diagram of study population.

Figure 2

Percent severity per group per test according to International Consensus Criteria presented per test per group. The two stacked upper columns show the unchanged group and the two stacked lower columns the worsening group. The results of test one are on the left, and the right the results of test two are on the right.

Figure 3

ROC analysis of the change in ICC severity scale to detect worsening symptoms. ICC: international consensus criteria of disease severity [1].

Figure 4

Percent cerebral blood flow change in both head-up tilt tests, comparing patients with a relatively stable clinical condition to those with a worsening condition. CBF: cerebral blood flow.

Figure 5

Percent cerebral blood flow individual changes in both head-up tilt tests comparing patients with a relatively stable clinical condition (blue) to those with a worsening condition (red). Unchanged condition meaning patients returning to patient care without a significant change in their clinical situation (blue; left sided panel) compared to worsening condition where patients returned for re-evaluation because of worsening symptomatology (red; right sided panel).

Figure 6

ROC analysis of the change in %CBF reduction to detect worsening symptoms. %CBF reduction: reduction in the percent cerebral blood flow during tilt testing.

Figure 7

Percent cerebral blood flow reduction in a ME/CFS patient group derived from two previous manuscripts divided by ICC disease severity [21,22]. Post hoc results F (2, 226) = 16.14 p < 0.0001; mild versus moderate p = 0.0007, mild versus severe p < 0.0001 and moderate versus severe p = 0.0073.