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Formula: A Diagnostic Marker for CFS?
Article: Naschitz JE et al. “The head-up tilt
test with haemodynamic instability score in diagnosing chronic fatigue
syndrome.” Q J Med. 2003; 96:133-142.
Synopsis: Researchers in Israel have tested the
haemodynamic instability score (HIS), a formula that uses measurements taken
during a head-up tilt test, to see if it can accurately distinguish patients
with chronic fatigue syndrome (CFS) from controls.
The HIS reflects blood pressure and heart rate changes during
the tilt test, which is used to determine the functioning of a patient’s
autonomic nervous system. A majority of people with CFS display some degree of
In this prospective controlled study, the researchers examined
40 patients with CFS and compared their HIS scores to those of 278 non-CFS
subjects with conditions that included fibromyalgia, syncope, generalized
anxiety disorder, essential hypertension, non-CFS chronic fatigue and Familial
Mediterranean Fever (FMF). Fifty-nine healthy subjects also were compared.
The results showed that the HIS was an effective tool in
differentiating CFS patients from the other study participants. Specifically,
90.3 percent of the CFS patients who completed the tilt test scored above the
threshold of HIS >-0.98. This compared to 21.4 percent of the non-CFS chronic
fatigue group; 17.9 percent of the syncope group; 13.2 percent of the
fibromyalgia group; 11.9 percent of the healthy controls; 8.0 percent of the FMF
group; and 3.6 percent of the hypertension group (p<0.0001 in all
comparisons). Only the anxiety group (45 percent) scored at a non-significant
The authors write that their results suggest a definable,
CFS-characteristic autonomic dysfunction may exist. They further contend that
“the presence of this distinctive dysautonomia in CFS, which is not usually
observed in other fatigue syndromes, lends support to the concept that CFS is a
separate entity among illnesses characterized by fatigue.”
Below is a brief question-and-answer
session with the study’s lead author, Jochanan E. Naschitz, M.D., associate
professor in medicine, Department of Internal Medicine,Bnai
Q: What are the potential benefits of your findings
to both researchers and health care providers?
Dr. Naschitz: On the head-up tilt test (HUTT), a
particular dysautonomia is revealed in CFS patients that differs from
dysautonomia in several other disorders. This distinct abnormality can be
identified by HIS >-0.981. To further support the prospect of
defining a characteristic dysautonomia in CFS patients, an additional
methodology was proposed to assess the cardiovascular reactivity during the
Beat-to-beat measurements of the heart rate (HR) and the pulse
transit time (PTT) were rendered. Ten-minute recording with the patient supine
was followed by recording 600 cardiac cycles on tilt, i.e., five to 10 minutes.
Data were processed by recurrence plot and fractal analysis. Fifty-two variables
were calculated in each subject. On multivariate analysis, the best predictors
of CFS were determined, and, based on these predictors, the ‘Fractal &
Recurrence Analysis-based Score’ (FRAS) was calculated2. The best
cut-off differentiating CFS from a mixed control population was FRAS = +0.22.
FRAS >+0.22 was associated with CFS (sensitivity 70% and specificity
The possibility of distinguishing the cardiovascular
reactivity of patients with CFS, with the aid of the HIS and FRAS, from
reactivity in patients with other functional somatic syndromes, such as
fibromyalgia3 and neurally mediated syncope, as described above,
tends to support that a CFS-characteristic dysautonomia may be operative. In
summary, four cross-sectional studies1,3-5 converge to support the
existence of a distinctive disease-specific dysautonomia in CFS patients.
Therefore, we submit that the HIS and FRAS may be used, in the
appropriate clinical context, to support the diagnosis of CFS, which until now,
could only be subjectively inferred. A pilot study suggested that midodrine
treatment, directed at the autonomic nervous system in CFS, results first in
correction of dysautonomia followed by improvement of fatigue. This finding
implies that dysautonomia is pivotal in the pathophysiology of CFS, at least in
a large part of the patients, and that manipulating the autonomic nervous system
may be effective in the treatment of CFS.
Q: How did you develop the HIS concept?
Dr. Naschitz: This question brings about
nostalgia. In the late 1990s we added to the standard head-up tilt test a
capnography channel to enable diagnosis of hyperven-tilation and called this
method “capnography head-up tilt test” (CHUTT)6,7. (Capnogra-phy
involves measuring carbon dioxide levels in the expired breath.) The CHUTT was
subsequently applied to the study of CFS patients, since dysautonomia and
hyperventilation were the mechanisms supposed to be involved in the pathogenesis
On CHUTT, vasodepressor reaction, cardioinhibitory reaction,
orthostatic hypotension, postural tachycardia syndrome, or hyperventilation
occurred in only half of CFS patients. Increased lability of blood pressure (BP)
and heart rate (HR) was perceived in all subjects on HUTT. However, there was no
appropriate measure to express these findings. The following study was
undertaken in order to define objective and precise parameters of hemodynamic
instability on postural challenge. Our proposed method involves computation of
BP and HR changes during HUTT, followed by processing of the data by novel image
analysis methods. An equation was deduced to calculate the hemodynamic
instability score (HIS) in the individual patient: HIS = 64.3303 +
(SYST-FD.abs x -68.0135) + (SYST-SD.cur x 111.3726) + (HR-SD.cur
x 60.4164). The best cut-off differentiating CFS from healthy was –0.98.
HIS values >-0.98 were associated with CFS (sensitivity 97% specificity
96.6%). The drawback of the HIS is the prerequisite that 30 minutes of HUTT is
completed. If the tilt is prematurely terminated because of a symptomatic event,
as it occurs in almost one third of CFS patients, the HIS cannot be
Subsequent studies validated the HIS3,4, improved
the technique5, shortened the duration of the tilt phase, thus
practically eliminating tilt drop-outs2.
Q: What comes next for you and your research
Dr. Naschitz: First, treatment of CFS by
manipulating the autonomic nervous system. We hypothesized that midodrine
treatment could benefit patients with the CFS. Ten patients with CFS and five
control patients with non-CFS fatigue were studied. The patients were off
medications for at least two weeks before entering the study. A dysautonomic
reaction on HUTT (i.e., HIS >-0.98) was present in all CFS but not in the
non-CFS control patients. With midodrine treatment, six of 10 CFS patients
showed subjective and objective improvement, which was maintained during 12
months of treatment. On last HUTT the average HIS was -1.51 (range from -0.87 to
-1.98). Non-CFS fatigue patients, with normal HIS at baseline, had no
improvement in HIS and fatigue scores while taking midodrine9.
Results of this pilot study spurs larger prospective studies on the principle of
manipulating the autonomic nervous system to improve both dysautonomic phenomena
and fatigue in CFS.
Second, separating fibromyalgia from CFS. Distinction between
fibromyalgia and CFS could be possible based on their cardiovascular
Third, developing an objective test in support of the
diagnosis of FMF based on its specific cardiovascular reactivity. Finally,
examination of additional groups of patients with “somatic functional syndromes”
in searching for disease-specific cardiovascular reactivity patterns.
Editor’s note: The authors acknowledge limits to their
present study. Fifty-six HUTT examinations were terminated because of syncope or
presyncope, including nine in the CFS group.
1) Naschitz JE
et al. Hemodynamic instability in chronic fatigue syndrome: indices and
diagnostic significance. Semin Arthritis Rheum. 2001;31:199-208.
JE, Sabo E, Naschitz S, Rozenbaum M, Rosner I, Musafia-Priselac R, Shaviv N,
Ahdoot A, Ahdoot M, Gaitini L, Eldar S, Yeshurun D. Fractal Analysis and
Recurrence Quantification Analysis of Heart Rate and Pulse Transit Time for
Diagnosing Chronic Fatigue Syndrome. Clin Autonomic Res.
JE, et al. Cardiovascular response to upright tilt in fibromyalgia differs from
that in chronic fatigue syndrome. J Rheumatol. 2001;28:1356-1360.
JE, Sabo E, Naschitz S, Rosner I, Rozenbaum M, Fields M, Isseroff H, Musafia
Priselac R, Gaitini L, Eldar S, Zukerman E, Yeshurun D. Hemodynamic Instability
Score in Chronic Fatigue Syndrome (CFS) and non-CFS Chronic Fatigue. Semin
Arthritis Rheum. 2002;32:141-148.
JE, Rosner I, Rozenbaum M, Naschitz S, Shaviv N, Fields M, Isseroff H, Zuckerman
E, Yeshurun D, Sabo E. The head-up tilt test with hemodynamic instability score
in diagnosing chronic fatigue syndrome. Q J Med. 2003;96:133-142.
JE, Gaitini L, Eridzhanyan L, Keren D, Sabo E, Yeshurun D, Hardoff D, Yaffe M.
The capnography tilt test for the diagnosis of hyperventilation syncope. Q J
JE, Hardoff D, Bystritzki I, Yeshurun D, Gaitini L, Tamir A, Yaffe M. The role
of the capnography head-up tilt test in the diagnosis of syncope in children and
adolescents. Pediatrics. 1998:101:1-6.
JE, Rosner I, Rosenbaum M, Gaitini L, Bistritzki I, Zuckerman E, Sabo E,
Yeshurun D. The capnography head-up tilt test for evaluation of chronic fatigue
syndrome. Semin Arthritis Rheum. 2000;30:79-86.
JE, Rosner J, Rozenbaum M, Musafia Priselac R, Sabo E, Gaitini L, Eldar S,
Zukerman E, Yeshurun D. Successful Treatment of Chronic Fatigue Syndrome with
Midodrine: a Pilot Study. Clin Exp Rheumato. In press.