Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients have a high prevalence of orthostatic intolerance [1
]. In a study of 429 adult ME/CFS patients, we recently demonstrated that 86% had orthostatic intolerance symptoms during daily life. Moreover, during a 30-min head-up tilt table test, 90% had an abnormal cerebral blood flow (CBF) reduction as assessed by extracranial Doppler measurements [2
]. This abnormal CBF reduction was not only present in ME/CFS patients with well-defined heart rate and blood pressure abnormalities during tilt testing, like orthostatic hypotension, postural orthostatic tachycardia syndrome (POTS) and syncope [4
], but also in ME/CFS patients with a normal heart rate and blood pressure response to upright posture [2
]. The mean CBF reduction of 26% in the entire study population with ME/CFS was significantly different from the 7% reduction observed in healthy controls in response to the same orthostatic stress.
Documenting an abnormal cerebral blood flow is helpful in guiding therapy for orthostatic intolerance (OI). As described in the IOM report: “Orthostatic intolerance is defined as a clinical condition in which symptoms worsen upon assuming and maintaining upright posture and are ameliorated (although not necessarily abolished) by recumbency” [1
]. Symptoms of orthostatic intolerance sought in the history of patients “are those caused primarily by [1
] cerebral underperfusion (such as light-headedness, near-syncope or syncope, impaired concentration, headaches, and dimming or blurring of vision), or [2
] sympathetic nervous system activation (such as forceful beating of the heart, palpitations, tremulousness, and chest pain. Other common signs and symptoms of orthostatic intolerance are fatigue, a feeling of weakness, intolerance of low-impact exercise, nausea, abdominal pain, facial pallor, nervousness, and shortness of breath”.
A limitation of the extracranial Doppler measurements is that image acquisition lasts between 2 and 7 min [2
]. In our recent study, patients were excluded if they were unable to maintain the upright position during the acquisition period, and also if a rapid drop in heart rate and blood pressure prevented complete image acquisition. Moreover, patients can develop post-exertional malaise after conventional 60–90 degree head-up orthostatic stress testing [1
]. Due to these problems—image acquisition time, the potential for post-exertional malaise and inability to stand long enough— conventional orthostatic testing may not be advisable in severe ME/CFS patients. Moreover, in previous work, we showed that 15 of 444 patients could not complete standing during the head-up tilt test [2
]. Wyller et al. described a different method of orthostatic stress testing [7
], which involved a low-grade head-up tilt test of 20 degrees in 27 ME/CFS adolescents. The rationale was that a 70 degree head-up tilt testing is associated with a high rate of false-positive results in adolescents. Using the 20 degree tilt over a period of 15 min, the authors showed that heart rate, blood pressure and stroke volume index changes were different in ME/CFS adolescents when compared with age- and gender-matched controls.
Assuming that severe ME/CFS patients cannot tolerate prolonged standing during tilt testing and may have more hemodynamic abnormalities including a rapid decline of blood pressure, the aim of the current study was to test the hypothesis that reduced cerebral blood flow and reduced stroke volume index/cardiac index could also be confirmed in severe ME/CFS patients during 15 min of low-grade (20 degree) head-up tilt testing.
The main finding of this exploratory study is that in severe ME/CFS patients, a significant reduction in cerebral blood flow can be provoked during a brief 20 degree head-up tilt test. The combination of low-grade head-up tilt testing and extracranial Doppler echography has not been described before. The 27% reduction in cerebral blood flow after 15 min compares to the 26% reduction observed after 30 min of 70 degree head-up tilt in a less severely affected population of ME/CFS patients [2
]. We also observed a significant reduction in stroke volume index during this mild orthostatic stress, and found a significant correlation between the decrease in cardiac index and the decrease in cerebral blood flow. Finally, even with this low orthostatic stress, four patients fulfilled the heart rate criteria for POTS, while none of the patients had an orthostatic hypotension or (near) syncope. A milder orthostatic stress of 20 degrees also allowed the accurate measurement of CBF declines that might have been difficult to measure in those who have rapid drops in blood pressure associated with classical orthostatic hypotension or vasovagal syncope when tested at 70 degrees [2
]. It remains to be determined whether a 20 degree tilt angle would be adequate for the diagnosis of orthostatic intolerance/significant cerebral blood flow reduction in less severely affected ME/CFS patients.
A previous study with 20 degree head-up tilt testing for 15 min in adolescent CFS patients showed a significantly higher heart rate and lower stroke volume index early after tilting (0.5–2.5 min after onset of tilt) in CFS patients compared with controls [7
]. The present study in adults confirms the changes in stroke volume index during 20 degree tilt testing in CFS adolescents. Remarkably, supine heart rates were higher in our patient population (mean 35 years) than in the adolescent CFS population of Wyller et al. (mean 15 years) [7
]. A large scale population study in healthy participants showed that resting heart rate in 15 year old adolescents normally is slightly higher than in adults over 20 years [14
]. Our observation of a higher resting heart rate in the severe ME/CFS patient population might be related to disease severity, with a higher heart rate in more severe patients. However, this needs to be studied in a larger sample size.
It is generally assumed that part of the OI symptomatology is related to cerebral hypoperfusion [4
]. One technique to study cerebral perfusion is transcranial Doppler. Using this technique, OH and POTS have been studied in different diseases and under different physiological conditions like aging, high-altitude, space flights and heat stress [17
] However, it has been noted that OI symptoms during HUT may be present, even in the absence of abnormalities of heart rate or blood pressure [33
]. Three recent studies used transcranial Doppler to investigate cerebral perfusion in patients with a normal HUT and without an abnormal HR and BP response like POTS or OH [33
]. The three studies found that the blood flow velocity decrease in patients with a normal HUT but with OI symptoms was larger than in healthy volunteers and patients without OI, and similar to the patients with POTS or OH. These observations suggest that cerebral hypoperfusion is not only present in POTS and OH patients, but also in patients with OI symptoms without POTS and OH.
Several points about the study findings deserve emphasis. First, in our earlier study using a 70 degree tilt test, the decrease in stroke volume index was 31% at 15 min post tilt with no differences between mild, moderately and severely affected ME/CFS patients [10
]. The stroke volume index decrease in the present study was 30%. This suggests that mild orthostatic stress testing in severe ME/CFS patients results in similar stroke volume index reductions when compared to 70 degree testing in ME/CFS patients of less severe disease. Further studies are needed to compare stroke volume changes at the different tilt angles in this patient population with varying degrees of disease severity.
Second, in a previous study, we found that cerebral blood flow reduction was 26% during a 70 degree tilt test [2
]. In the present study, a cerebral blood flow decrease of 27% was observed. In contrast, studies using transcranial Doppler have shown no differences in cerebral blood flow velocities between CFS patients and healthy controls both at low-grade and high-grade tilt angles [37
]. However, the authors showed that the end-tidal CO2
values were lower in CFS patients compared with controls, at all tilt angles. Previous studies have shown that hypocapnia can reduce intracranial vessel diameters, thereby altering the relation between flow velocity changes and hemodynamic changes [38
]. Therefore, the absence of a difference in cerebral blood flow velocities of patients versus controls using transcranial Doppler may be related to end-tidal CO2
-related vasoconstriction of the middle cerebral artery in CFS patients. Vasoconstriction leads to increases in cerebral flow velocities, resulting in non-significant differences in the TCD measurement between CFS patients and controls. The more direct measurement using extracranial Doppler identifies the global reduction in CBF that can be missed with transcranial Doppler. The similarity of cerebral blood flow reduction in the present study and our previous study despite the lower degree of orthostatic stress and the shorter tilt is most likely related to the more severe disease status of patients in the present study [2
]. Consistent with our previous study [2
], the results of this study again clearly demonstrate that reduced cerebral blood flow is a cardinal contributor to orthostatic intolerance symptoms in ME/CFS patients.
Third, as seen in our previous study and other recent studies using transcranial Doppler, we again demonstrated that an orthostatic intolerance/abnormal cerebral blood flow reduction may be present without heart rate and blood pressure abnormalities [2
]. Patients with a normal heart rate and blood pressure response during a tilt test would have been misclassified as having no abnormalities. The present study suggests that cerebral blood flow measurements are needed in order to more accurately measure the prevalence of orthostatic intolerance in ME/CFS patients.
Fourth, the data of this study extend the observation that hypocapnia is significant in ME/CFS patients and is a likely contributor to reductions in cerebral blood flow [2
]. The end-tidal CO2
reductions also support the observation that 20 degrees is sufficient to provoke similar cerebral blood flow changes in severe ME/CFS patients compared with a less severely diseased group of ME/CFS. When hypocapnia is observed, a focus on respiration depth and speed has the potential to be one of the therapeutic guidance options for these patients to lessen orthostatic intolerance complaints. Another possible factor besides vasculature, autonomic nervous system and end-tidal CO2
might be altered blood cell behavior, especially red blood cell [42
Fifth, in a previous review on the relation between acute cardiac output changes and cerebral blood flow changes, Meng et al. found in healthy volunteers that a 30% reduction in cardiac output resulted in a 10% reduction in cerebral blood flow [44
]. In the present study, we also found a significant relation between the reduction in cardiac index and cerebral blood flow. This provides further evidence for the validity of the extracranial Doppler measurements to determine cerebral blood flow. Furthermore, from the linear regression analysis in the present study, we calculated that a 30% reduction in cardiac index resulted in a 28% reduction in cerebral blood flow, which is much larger than the 10% in healthy volunteers in the review of Meng et al. [44
]. Whether these differences are specific to ME/CFS are related to the use of transcranial Doppler vs. extracranial Doppler or are related to the significant reductions in end-tidal CO2
in the present study will need to be determined in future and larger studies.
Finally, even during a brief 20 degree tilt, four (21%) patients developed POTS. This has not been described before and might be a reflection of the severity of the disease. It also implies that the diagnosis of POTS cannot be dismissed when patients have complaints suggestive of POTS in non-standing positions like sitting or lying down with a slight head-up position.
4.1. Clinical Implications
Patients are advised to lie down when they experience orthostatic intolerance complaints. Our findings of a clinically significant cerebral blood flow reduction at just 20 degrees suggest that a slight head-up position may not be adequate enough to resolve symptoms of orthostatic intolerance in some patients. Furthermore, the European Society of Cardiology syncope guidelines and other papers advocate the use of a nocturnal head-up position of more than 10 degrees to prevent nocturnal polyuria and the consequent circulatory underfilling [45
]. In light of the presented results, this advice has the potential to be detrimental in some ME/CFS patients.
This study only included ME/CFS patients who were bedbound, and we caution that the 20 degree head-up tilt angle needs further study before it can replace longer 70 degree tilt angles for assessing less severely impaired ME/CFS patients. Comparisons of the hemodynamic and cerebral blood flow abnormalities of 20 and 70 degrees of tilting are needed. We also did not include healthy controls for comparison. It is possible that healthy controls would have little or no perturbation in response to a 20 degree head-up angle, which would have the effect of widening the physiologic differences between ME/CFS patients and controls. Whether disease severity differences lead to differences in cerebral blood flow reduction needs to be studied in the future. Finally, while it is reasonable to expect that the 20 degree abbreviated tilt test would be less taxing than a longer 70 degree tilt test, and therefore less likely to provoke post-exertional malaise, this hypothesis remains to be tested.