Orthostatic Intolerance in Chronic Fatigue Syndrome

The American Journal of Medicine, Volume 120, Issue 3, Page e13 
(March 2007)

Peter C. Rowe, MDa, Katherine E. Lucas, PhDb

Affiliations:
[a] Department of Pediatrics, Johns Hopkins University School of Medicine, 
Baltimore, MD USA
[b] Department of Pediatrics, Johns Hopkins University School of Medicine, 
Department of Epidemiology, Johns Hopkins University Bloomberg School of 
Public Health, Baltimore, MD USA

NLM Citation: PMID: 17349421


To the Editor:

The main outcome measure in Jones and colleagues' study of the prevalence 
of orthostatic intolerance in subjects with chronic fatigue syndrome (CFS)1 
was a 45-minute head-up tilt test, performed after exclusion of subjects 
with other medical conditions and subjects being treated with medications 
used to treat orthostatic intolerance. These exclusions were 
methodologically necessary to ensure that the observed rate of orthostatic 
intolerance was associated with CFS and not with the co-morbid medical 
conditions, and that medication use did not partially treat (and therefore 
obscure detection of) the underlying circulatory abnormalities.

The exclusions came at a steep methodologic cost to the representativeness 
of the sample. After the exclusion of 41 subjects, and refusal to 
participate by 23 more, the tilt portion of the study evaluated 10 
subjects, just 14% of the original group of 74. The sample was entirely too 
small to allow firm conclusions to be drawn about the prevalence of 
orthostatic intolerance overall in those with CFS, or about the relative 
prevalence of postural tachycardia or neurally mediated hypotension in this 
group.

While not the main focus of the article, Table 7 summarizing the literature 
on orthostatic intolerance in those with CFS is incomplete. In addition to 
the small study by DeLorenzo and colleagues of 5 patients with postural 
tachycardia (reference 10 in the Table), the authors may not have known of 
a larger study by the same group. That study enrolled 78 subjects with CFS, 
22 of whom (28%) developed hypotension during tilt, versus 0 of 38 controls.2
We would also like to clarify the data abstracted in Table 7 from our 
randomized trial of fludrocortisone (reference 13). Among 171 with CFS who 
underwent tilt testing, the rate of neurally mediated hypotension was 62%; 
a further 4% met criteria for postural tachycardia syndrome alone. The 
combined prevalence of orthostatic intolerance was 66%, not 62% as reported 
in Table 7. Those who did not develop hypotension were excluded from the 
treatment portion of the randomized trial, but none of the 171 eligible 
subjects was excluded from the data on the prevalence of orthostatic 
abnormalities. We therefore are not sure what the authors meant by the 
notation "77% excluded." Table 7 also includes some minor typographical 
errors: reference 20 appears twice (it should be reference 21 the first 
time, then reference 8 the second time), and reference 34 in Table 7 should 
be reference 37.

Any debate about the precise prevalence of postural tachycardia syndrome or 
neurally mediated hypotension in CFS has the potential to neglect a 
critical point. In our studies of orthostatic intolerance, now totaling 
over 220 subjects with CFS, quiet upright posture has been a strong and 
consistent physiologic stressor in over 95%. Even when not accompanied by 
hemodynamic changes, orthostatic stress typically has been associated with 
a provocation or exacerbation of characteristic CFS symptoms. Others have 
shown that these symptoms and hemodynamic abnormalities with orthostatic 
stress can be reversed upon application of external lower-body compression 
(reference 37). Whether orthostatic disorders are primary or secondary, 
this evidence suggests that they play an important contributing role in the 
phenomenology of the illness for a substantial proportion of affected 
individuals. In contrast to Jones and colleagues, we would agree with 
Freeman that a better understanding of the mechanisms of the disordered 
response to orthostatic stress would go a long way toward improving our 
understanding of the pathophysiology and treatment of CFS symptoms.3
References

1. Jones JF, Nicholson A, Nisenbaum R, et al.. Orthostatic instability in a 
population-based study of chronic fatigue syndrome. Am J Med. 
2005;118:1415e19-1415e28. Abstract: 
http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0512D&L=CO-CURE&P=R1014
2. De Lorenzo F, Hargreaves J, Kakkar VV. Pathogenesis and management of 
delayed orthostatic hypotension in patients with chronic fatigue syndrome. 
Clin Auton Res. 1997;7:185-190.
3. Freeman R. The chronic fatigue syndrome is a disease of the autonomic 
nervous system (Sometimes). Clin Auton Res. 2002;12:231-233.


© 2007 Elsevier Inc. All rights reserved.