Q J Med 2003; 96:133–142

doi:10.1093/qjmed/hcg018

The head-up tilt test with haemodynamic instability score

in diagnosing chronic fatigue syndrome
J.E. NASCHITZ, I. ROSNER 1 , M. ROZENBAUM 1 , S. NASCHITZ,
R. MUSAFIA-PRISELAC, N. SHAVIV, M. FIELDS, H. ISSEROFF, E. ZUCKERMAN,
D. YESHURUN and E. SABO
From the Departments of Internal Medicine A and 1Rheumatology, Bnai Zion Medical
Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of
Technology, Haifa, Israel

Received 28 May 2002 and in revised form 2 December 2002

Summary
Background: Studying patients with chronic
fatigue syndrome (CFS), we have developed a
method that uses a head-up tilt test (HUTT) to
estimate BP and HR instability during tilt, expressed
as a ‘haemodynamic instability score’ (HIS).
Aim: To assess HIS sensitivity and specificity in the
diagnosis of CFS.
Design: Prospective controlled study.
Methods: Patients with CFS (n = 40), non-CFS
chronic fatigue (n = 73), fibromyalgia (n = 41),
neurally mediated syncope (n = 58), generalized
anxiety disorder (n = 28), familial Mediterranean
fever (n = 50), arterial hypertension (n = 28), and
healthy subjects (n = 59) were evaluated with a
standardized head-up tilt test (HUTT). The HIS was
calculated from blood pressure (BP) and heart rate
(HR) changes during the HUTT.
Results: The tilt was prematurely terminated in
22% of CFS patients when postural symptoms
occurred and the HIS could not be calculated. In
the remainder, the median(IQR) HIS values were:
CFS q2.14(4.67), non-CFS fatigue !3.98(5.35),
fibromyalgia !2.81(2.62), syncope !3.7(4.36),
generalized anxiety disorder !0.21(6.05), healthy
controls !2.66(3.14), FMF !5.09(6.41), hyperten-
sives !5.35(2.74) (p-0.0001 vs. CFS in all groups,
except for anxiety disorder, p=NS). The sensitivity
for CFS at HIS )!0.98 cut-off was 90.3% and the
overall specificity was 84.5%.
Discussion: There is a particular dysautonomia
in CFS that differs from dysautonomia in other
disorders, characterized by HIS )!0.98. The
HIS can reinforce the clinician’s diagnosis by
providing objective criteria for the assessment of
CFS, which until now, could only be subjectively
inferred.

Introduction
Clinically evaluated, medically unexplained fatigue
of at least 6 months duration, that is of new onset, is
not a result of ongoing exertion, not substantially
alleviated by rest, and that substantially reduces
previous levels of activity, is called chronic fatigue
syndrome (CFS).1 Other prominent features of the
syndrome are chronic and recurrent low-grade
fever, pharyngitis, lymphadenopathy, arthralgia
and neuropsychological symptoms. The prevalence
of CFS is 0.07–0.2% of the population.2 The
aetiology and pathogenesis of CFS are poorly
understood.
Previous studies have documented a close
connection between impairment of autonomic
functions, i.e. dysautonomia, and CFS.2–7 Abnor-
malities of central nervous system on magnetic

Address correspondence to Dr J.E. Naschitz, Department of Internal Medicine A, Bnai Zion Medical Center, Haifa
31048, PO Box 4940, Israel. e-mail: Naschitz@tx.technion.ac.il
! Association of Physicians 2003
134 J.E. Naschitz et al.
resonance imaging9 and single-photon emission
tomography,10 as well as disruption of the
hypothalamic-pituitary-adrenal axis and sero-
toninergic and noradrenergic pathways have been
demonstrated,11,12 and a ‘distal dysautonomia’
has been described in CFS patients.13
As the fast response of the blood pressure (BP)
and heart rate (HR) to acute stimuli is under
autonomic nervous control, BP and HR measure-
ments during orthostatic challenge can be used as
one measure of cardiovascular autonomic activity.
For this purpose, the head-up tilt test (HUTT) is
used. Classical pathological reactions to the HUTT
are: vasodepressor reaction, cardioinhibitory reac-
tion, orthostatic hypotension and postural tachy-
cardia syndrome. In studies using these outcome
measures, evidence for abnormal cardiovascular
reactivity was found in one half of CFS patients. The
latter measures are non-specific, however, and also
occur in a variety of disorders unrelated to CFS.3–8
HR variability during the HUTT is another measure
of cardiovascular reactivity in CFS.14,15 As with the
classical outcomes of the HUTT, abnormalities of
HR variability in CFS are not specific for this
disorder.16,17 A third method, recently proposed for
the study of the cardiovascular reactivity of CFS
patients involves computing BP and HR changes
during the course of a HUTT, followed by proces-
sing the data by image analysis methods. These data
receive numerical expression as the ‘haemo-
dynamic instability score’ (HIS). In our previous
study,18,19 the best cut-off differentiating CFS from
healthy patients was HIS !0.98. HIS values above
!0.98 were associated with CFS (sensitivity 97%,
specificity 96.6%). In a second study, we applied
the proposed HIS threshold of !0.98 to study
populations which served as ‘test groups’.19 In the
‘test groups’, similarly to the earlier ‘training
groups’, the HIS threshold of !0.98 differentiated
between CFS patients (HIS = q2.02, SD 4.07) and
healthy subjects (HIS = !2.48, SD 4.07).19 HIS
values higher than !0.98 were usually associated
with CFS.18–20
The diagnosis of CFS rests largely on patient
history. In any illness defined by a group of
symptoms, two questions arise: do the patients in
fact report the symptoms that investigators say they
should, and do those symptoms distinguish patients
with CFS from other fatiguing illnesses?2 Two
studies have validated the CFS questionnaires: the
symptoms of CFS, but not the control symptoms, are
much more frequently reported by patients with
CFS than by patients with other diseases which
produce fatigue.21,22 However, the differentiation of
CFS from the other functional somatic syndromes,
fibromyalgia and myofascial pain syndrome, may
be difficult, because features of these three dis-
orders can overlap.23 No physical finding or labor-
atory test is generally accepted or in common use to
strengthen the diagnosis of CFS.3,4 Two develop-
ments might advance the diagnosis of CFS. The first
is based on a recent study showing that 72% of
subjects in a group of patients with CFS had
increased plasma levels of an abnormal 37 kDa
protein.24 The possible application of this finding
for diagnostic purposes has not been appraised. The
second development is evaluation of dysautonomia
as a possible marker of CFS. A diagnostic role for
the HUTT classical endpoints, as well as for spectral
analysis of HR and BP variability in patients with
CFS, has not been defined,2,8,16,17 although we
have previously suggested that the HIS may be
useful in confirming the diagnosis of CFS.18–20 In
the present study, we reassessed the sensitivity of
HIS )!0.98 for the diagnosis of CFS in a new
group of CFS patients. The reproducibility of the HIS
on repeated examinations was evaluated. Speci-
ficity for the diagnosis of CFS was evaluated in
comparison with controls, some exhibiting shared
clinical features with CFS (patients with non-CFS
chronic fatigue, fibromyalgia, generalized anxiety
disorder, neurally mediated syncope) and others not
suffering from fatigue (patients with Familial
Mediterranean Fever, essential hypertension, healthy
subjects).
Methods
All participants gave informed consent, and our
institution’s committee for human research app-
roved the study. All patients were fully ambulatory
at the time of the study. The patients were not taking
medications for at least 2 weeks before the study.
Technicians carrying out the HUTT were informed
as to the patients’ diagnosis, but did not know of the
intention to compare between the groups. Data of
earlier studies, which used somewhat different
equations and were based upon slightly different
dependent measures18,20,25 were revised, expanded
and processed according to the latest equation.18
Patients
CFS patients (n = 40) were consecutive subjects
referred from a CFS clinic for evaluation with the
HUTT. All patients met the Centers of Disease
Control and Prevention definition1 of CFS, had no
other diagnosable medical or psychiatric illness to
explain their symptoms, and did not have fibro-
myalgia (FM), based on a specific tender points
count -11/18.26 The subjects’ median age was 27
 Diagnosing CFS
years (range 20–71 years) and the M:F ratio was
12:28. The median duration of illness was 16.7
months (range 7 months to 4 years). All patients had
moderate fatigue at rest and severe fatigue with
exertion. The patients’ mean fatigue impact score27
was 69.1 (SD 12.8). The fatigue impact score
examines the patients’ perception of the functional
limitations that fatigue has caused over several
months. Subjects are asked to rate the extent to
which fatigue has caused problems for them in
relation to exemplar statements, and each item is
quantified on a scale of 0-3: 0, no problem to 3,
extreme problem. The fatigue impact score includes
three subscales to assess perceived fatigue impact
on cognitive functioning (10 items), physical func-
tioning (10 items), and psychosocial functioning (20
items). The maximum score is 120. Healthy persons
score -20.
Patients with non-CFS chronic fatigue (n = 73)
were consecutive subjects referred from a CFS
clinic. Similarly to the CFS patients, they com-
plained of fatigue of new onset,28 not a result of
ongoing exertion, not substantially alleviated by
rest, associated with substantial reduction in pre-
vious levels of activity, and lasting 3 months or
more, but they did not otherwise meet the definition
criteria of CFS. The subjects’ median age was 38
years (range 19–65 years) and the M:F ratio was
24:49. Median duration of illness was 7 months
(range 3–13 months). The patients’ mean fatigue
impact score was 69.3 (SD 10.2).
Syncope patients (n = 58) were consecutive sub-
jects referred for HUTT for evaluation of syncope of
unknown cause. All subjects had two or more syn-
copal or presyncopal spells during the previous
3 months. Patients with co-morbidities, inclusive
CFS were excluded. Fifteen subjects reported
chronic fatigue. The subjects’ median age was
24 years (range 18–48 years) and the M:F ratio
was 18:40. The diagnosis of neurally mediated
syncope29 was eventually established.
Fibromyalgia (FM) patients (n = 41) were referred
from a rheumatology clinic. The diagnosis of FM
was based on criteria of the American College of
Rheumatology for FM.26 Sixteen subjects who also
reported fatigue but did not meet the diagnosis of
CFS were included. The patients’ median age was
30 years (range 22–67) and the M:F ratio was 13:28.
Generalized anxiety disorder patients (30)
(n = 28) were referred from a psychiatry clinic.
They had a history of palpitation and atypical chest
pain, but no symptoms consistent with CFS, FM or
other co-morbidities. The patients’ mean age was
31.4 years (SD 8.8) and 75% patients were women.
Familial Mediterranean Fever (FMF) patients
(n = 50) were referred from an adult rheumatology
135
clinic. The patients had recovered from the last
attack of FMF31 at least 14 days before the HUTT.
Patients with co-morbidities were excluded. The
patients’ median age was 30 years (range 21–60
years) and the M:F ratio was 25:25.
Essential hypertension (HT) patients (n = 28)
included subjects with mild to moderate systolic
and diastolic hypertension (HT) according to
criteria of the Sixth Joint National Committee on
Detection, Evaluation and Treatment of High Blood
Pressure.32 Patients had normal chest X-rays and
electrocardiograms. Their median age was 29 years
(range 18–49 years) and the M:F ratio was 9:19.
Healthy control subjects (n = 59) were physicians
and paramedics working on the medical ward, who
volunteered to participate in the study. Subjects
were eligible if they did not report persistent fatigue
or syncope during the preceding 12 months, and
had normal findings on physical examination,
routine laboratory tests, chest X-rays, and electro-
cardiogram. Their median age was 27 years (range
23–54 years) and the M:F ratio was 31:28.
The patient age was significantly higher in the
non-CFS group compared to all other groups
(p-0.01). Male predominance in the group of
healthy subjects was statistically significant only in
comparison to the CFS patients group (p-0.05).
Computation of the haemodynamic
instability score (HIS)
The protocol of the HUTT was based on the 10-min
supine/30-min head-up tilt test as previously
described.18 Testing was conducted from 0800 h
to 1100 h, in a quiet environment, and at constant
room temperature of 22–25 8C. The patients main-
tained a regular meal schedule, but were restricted
from smoking and caffeine ingestion for 6 h prior to
the examination. Intake of food products and
medications with sympathomimetic activity prior
to the study was prohibited.
Manual BP readings were taken by a physician
certified in the BP measurement technique
according to American Heart Association recom-
mendations.33 We favoured the mercury column
sphygmomanometer (Baumanometer, standby
model 0661–0250), since this is the standard non-
invasive method for BP measurement, and is the
most accurate for evaluation of BP at rest34 and
during HUTT.35 The HR measurements were
recorded on an electrocardiographic monitor. The
patient lay in a supine position on the tilt table,
secured to the table at the chest, hips and knees
with adhesive girdles. The cuff of the BP recording
device was attached to the left arm, which was
136 J.E. Naschitz et al.
supported at heart level at all times during the study.
Three measurements in the supine position were
recorded at 5-min intervals. The table was then
gently tilted head-up to an angle of 70 8C. The
duration of the tilt was 30 min. During the initial
5 min of tilt, measurements were obtained at 1-min
intervals, followed by readings every 5 min. When
dizziness or faintness occurred, repeated measure-
ments were taken at 30-s intervals. In the event of a
loss of consciousness, the test was discontinued.
Measures to avoid inaccuracies in processing the
HIS were strictly followed (Appendix).
The HIS was computed based on BP and HR-
differences along the HUTT.18 The ‘BP differences’
and ‘HR differences’ were computed (Figure 1).
Systolic and diastolic BP-differences were defined
as the differences between individual BP values
measured during HUTT and the last recumbent
BP value, and divided by the last recumbent BP
value. The result is BP difference, expressed as a
relative value by comparison to the last supine
Figure 1. Processing the HIS. Systolic and diastolic
BP, and HR values of a healthy subject, taken throughout
the HUTT. Supine measurements at 1, 5 and 10 min
of recumbence are labelled n1 to n3, while head-up
measurements at minutes 1, 2, 3, 4, 5, 10, 15, 20, 25 and
30 of tilt are labelled n4 to n13. From the measured values
(a), the relative changes of BP and HR were calculated,
according to the equation: BP difference = (BP(n1....n13)–
BPn3)/BPn3. Absolute values were then obtained by
converting all results to positive numbers. Shown in the
table are systolic BP differences as current (-c) and
absolute (-a) values, as well as HR differences in current
values (-c). The BP and HR changes were used to
calculate the SYS-DIFF-c-SD and HR-DIFF-c-SD (c),
which are independent predictors of the HIS. The third
independent predictor of HIS is the SYS-DIFF-a-FD, and
is processed from the time-curve of the systolic BP
differences (b) by a fractal analysis program. Finally, the
three independent predictors are applied to Equation 2
to compute the HIS (c). In this specific case, HIS
!3.184 is typical for a healthy person.
measurement, and calculated according to the
following equation:
BP difference=(BP(n1::::n13) {BPn3 )=BPn3 ð1Þ
The means and SDs of the current values of the
systolic and diastolic BP differences were calcu-
lated for each subject. The BP differences were also
represented graphically in time-curves. These figures
were constructed in a fixed template on Microsoft
Excel graphics. The frame measured two standard
rectangles on the horizontal axis (72 pixels width
each) and 12 rectangles on the vertical axis (21
pixels height each). The x-axis was calibrated from
1 to 13, representing the sequentially fixed mea-
surements. The y-axis was calibrated from 0 to 0.6,
representing the amplitude of the BP change. The
default of the time-curves was set so that BP
differences -0.02 were represented as = 0.02,
and BP differences )0.6 as = 0.6. The time-
curves were depicted as continuous, thin, black
lines on white background. Subsequently, MS Paint
was used to invert the original colours to white line
on black background. The images were then saved
as 3203320-pixel 24-bit bitmap images and loaded
into the computerized image analyser Benoit Ver-
sion 1.3 (Trusoft). The time-curve’s fractal dimen-
sion (FD) was automatically assessed by using
the box counting method. FD represents a ‘self-
similarity’ in dynamic behaviour over multiple
scales of time. FD is calculated as FD = log(number
of self-similar pieces)/log(magnification factor). The
side length of the largest box of the grid was
80 pixels. The coefficient of box size decrease was
1.3. The number of box sizes used was 17. The
increment of grid rotation was 158.
Absolute systolic and diastolic BP-differences
were computed by transforming positive and nega-
tive BP changes into positive values. The relative
values of BP differences were calculated as above.
HR differences were defined as the difference
between successive HR values and the last recum-
bent HR value, and divided by the last recumbent
HR value. The HR differences mean, SD and FD
were calculated. Absolute HR differences were
derived from the transformation of positive and
negative HR differences into positive numbers, and
were processed as for natural HR differences. On
multivariate analysis, the independent predictors
of CFS vs. healthy controls were: SYS-DIFF-a-FD,
the fractal dimension of absolute values of the
systolic BP differences; SYS-DIFF-c-SD, the stan-
dard deviation of the current values of the systolic
BP differences; and HR-DIFF-c-SD, the standard
deviation of the current values of the HR differences.
 Diagnosing CFS 137

!3.97 (4.61)

CFS, chronic fatigue syndrome; F, non-CFS fatigue; FM, fibromyalgia; Sy, recurrent neurally-mediated syncope; Anx, generalized anxiety disorder; H, healthy; FMF, familial
All non-CFS
Based on these three variables, the HIS was

47 (13.9%)

45 (15.5%)
-0.0001
calculated:

337

290
HIS=64:3303z(SYS-DIFF-a-FD3{68:0135)
z(SYS-DIFF-c-SD3111:3726) (2)

!5.35 (2.74)
zHR-DIFF-c-SD360:4164)

-0.0001
1 (3.6%)
According to the results of our previous study,18 the

HT

28

20
0
best cut-off differentiating CFS from healthy is HIS
!0.98. In that study, HIS values )!0.98 were

!5.09 (6.41)
associated with CFS (sensitivity 97% and specificity

-0.0001
4 (8.0%)
97%).

FMF

50

50
0

Mediterranean fever; HT, arterial hypertension. *HIS could be computed only for completed HUTT. **CFS vs. other groups.
Statistical analysis

!2.66 (3.14)
A non-parametric comparison between CFS patients

7 (11.9%)
-0.0001
and each other patient group was performed with
the Mann-Whitney U test. Multivariate analysis
using the logistic regression model was used to test

59

59
H

0
the groups’ adjustment for age and gender. Sen-
sitivity and specificity of the HIS cut-off )!0.98 for

!0.21 (4.36)
the diagnosis of CFS versus other disorders were
8 (28.6%)

9 (45%)
computed. Two-tailed p values of 0.05 or less were
considered to be statistically significant.
Anx

NS
28

20
!3.7 (4.36)
19 (32.7%)

Results
7 (17.9%)
-0.0001

The HUTT was prematurely terminated because of

58

39
Sy

presyncope or syncope in nine patients with CFS

(22.5%), in 17 patients with non-CFS fatigue
(23.3%), three patients with fibromyalgia (7.3%),
!2.81 (2.62)

5 (13.2%)

19 patients evaluated for recurrent faints (32.7%),

-0.0001
3 (7.3%)

and eight patients with generalized anxiety disorder

(28.6%). None of the healthy controls, patients with
FM

41

38

FMF or arterial hypertension patients developed

orthostatic symptoms. HIS could be calculated only
!3.98 (5.35)

in the subjects who completed the HUTT.

17 (23.3%)

12 (21.4%)
-0.0001

The HIS values in different patient groups are

HIS values in the different groups

shown in Table 1 and Figure 2. HIS values in CFS

73

56

were significantly different to those in the other

F

groups (p-0.0001), except for the group of patients

with generalized anxiety disorder, where differ-
28 (90.3%)
2.14 (4.67)
9 (22.5%)

-0.0001

ences were not significant. These results were not

affected by age and gender differences between the
CFS

groups, according to multivariate analysis of the

40

31

covariates.
The sensitivity of the HIS )!0.98 cut-off for CFS
Syncope on tilt (%)
Tilt completed (n)*

was 90.3%. The overall specificity of HIS )!0.98

Median(IQR) HIS

cut-off for CFS vs. all control groups was 84.5%.

Total patients

HIS)!0.98

The specificity of HIS )!0.98 for CFS vs. non-CFS

fatigue was 78.4%, vs. fibromyalgia 86.8%, vs.
Table 1

Group

generalized anxiety disorder 55%, vs. neurally medi-

p**

ated syncope 82.1%, vs. healthy subjects 88.1%,

138 J.E. Naschitz et al.
Figure 2. HIS values in the six patient groups. CFS,
chronic fatigue syndrome; F, non-CFS fatigue; FM,
fibromyalgia; ANX, generalized anxiety disorder; SY,
neurally mediated syncope; H, healthy subjects; FMF,
familial Mediterranean fever; HT, arterial hypertension.
The boxes contain the 50% of values falling between the
25th and 75th percentiles, the horizontal line within the
box represents the median value, and the ‘whiskers’ are
the lines that extend from the box to the highest and
lowest values, excluding the outliers. In CFS, the HIS
differed significantly from the HIS in other patient groups
(p-0.0001), except for generalized anxiety disorder.
vs. FMF 92%, and vs. essential hypertension
96.4%.
The reproducibility of the HIS was assessed with
reference to the !0.98 cutoff in 14 patients who
agreed to undergo repeated HUTT (Figure 3). These
included six patients with CFS, who had HIS
)!0.98 on initial examination as well as three
patients with non-CFS fatigue and six healthy
subjects, all having HIS -!0.98 on initial exam-
ination. Two to five HUTT examinations were
performed in each subject at one- to two-week
intervals, totalling 35 examinations performed in
Figure 3. HIS reproducibility with reference to the !0.98
cut-off. All subjects with HIS )!0.98 on initial examina-
tion also had HIS )!0.98 on repeat examinations, and
all subjects with HIS -!0.98 on initial examination had
HIS -!0.98 on repeat examinations. CFS, chronic
fatigue syndrome; F, non-CFS fatigue; H, healthy subjects.
the 14 patients. The HIS was correctly classified
with reference to the proposed cut-off in all
instances. Subjects with HIS )!0.98 on initial
examination also had HIS )!0.98 on re-testing and
subjects with HIS -!0.98 on initial examination
had similar values on repeated HUTT.
Discussion
The HUTT used in this study has been previously
applied to the investigation of dysautonomia in CFS
patients.4–8,15,17 but its use as a diagnostic tool in
CFS was not possible until the HIS was intro-
duced.18,19 The HIS cut-off )!0.98 usually dis-
tinguished CFS patients from other patient
populations. In the present study, 91.4% of our
CFS patients exhibited HIS values )!0.98.
The HIS differs from methods that assess cardio-
vascular reactivity by analysing absolute BP and HR
values36,37 rather than their changes. In our study,
the ‘BP differences’ indicated BP instability and ‘HR
differences’, HR instability. Since the BP differences
were corrected with respect to BP at baseline, a
direct comparison of values between hypertensives
and normotensives was possible. Similarly, the
correction of HR change with respect to baseline
HR values enabled comparison of subjects with
initial bradycardia or tachycardia. We used com-
puter-assisted image analysis to calculate the FD of
the time curves. Fractal measurements differ from
measurements used in regular Euclidean geome-
try.38,39 The FD represents a ‘self-similarity’ in
dynamic behaviour over multiple scales of time,
and can be seen as the minimum number of
underlying variables that are required to explain
the signal’s shape.
The HIS was characteristic of the diagnosis of
dysautonomia in CFS, and distinguished CFS from
several disorders that either display clinical similar-
ity with CFS or in which dysautonomia is known to
be present. The 90.3% sensitivity and 84.5%
overall specificity of HIS for CFS contrasts with
the merely moderate sensitivity and poor specificity
of classical autonomic testing for CFS.3–8,15–17
Though direct intraneural measurement of the
efferent sympathetic nerve traffic to blood vessels,
combined with spectral analysis of cardiovascular
reactivity during rest and postural challenge, has
advanced our understanding of the pathophysiology
of dysautonomia,40 these data are not specific for
CFS and have no application in the diagnosis of
CFS.41,42
To further support this observation, the ‘Fractal
and Recurrence Analysis Score’ was recently
 Diagnosing CFS
proposed.43 A 10-min supine phase of the HUTT
was followed by recording 600 cardiac cycles on
tilt, i.e. 5–10 min. Beat-to-beat HR and pulse transit
time were acquired. 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 and Recurrence Analysis-based Score’
(FRAS) was calculated. The best cut-off different-
iating CFS from the control population was
FRAS = q0.22. FRAS )q0.22 was associated
with CFS with 88% specificity and 70% sensitivity,
which is comparable with the figures for the HIS.
The difficulty in evaluating cardiovascular reactivity
by classical methods derives from the high degree
of non-linearity between external stimuli and
cardiovascular response that characterizes the
autonomic cardiovascular modulation. The pro-
posed solution to this problem uses joint quantifica-
tion of BP and HR fluctuations, and non-Euclidian
mathematical analysis: these methods were used in
computing the HIS and FRAS.
Classification of fatigue syndromes by HIS
values could be important in differentiating CFS
from other fatigue syndromes as well as in the
application of therapies directed at the autonomic
nervous system in patients who present with dys-
autonomia. Since dysautonomia is almost always
present in CFS patients, it has been proposed that
therapies which may counter the haemodynamic
disturbance in CFS could improve some of their
symptoms. Midodrine HCl, a potent a-1-adrenergic
agonist, is efficient in the treatment of haemo-
dynamic disturbances such as symptomatic ortho-
static hypotension, vasovagal syncope and postural
tachycardia syndrome.44 Ten patients with CFS and
five controls with non-CFS fatigue were studied. In
CFS patients receiving long-term treatment with
midodrine, a decrease in the HIS from q4.8 (range
q2.28 to q7.03) to !1.51 (range !0.87 to !4.2)
was paralleled by patients’ ability to return to
activities and subsequent remission of fatigue.
Patients with fatigue other than CFS did not
change on midodrine treatment (Naschitz et al,
personal communication).
Dysautonomia is often perceived as a ‘black box
of nebulous disorders’ compounded by poor
demarcation from variants of normality, sponta-
neous fluctuations in disease severity, and hetero-
geneity of clinical manifestations.45 It has been
suggested that patients with altered cardiovascular
regulation may be all part of a single continuum
of autonomic disturbances. Although there is con-
siderable overlap of symptoms, and a possible
common autonomic substrate linking patients with
139
disorders such as CFS, the postural hypotension
syndrome, neurally mediated syncope, and fibro-
myalgia, there are considerable differences bet-
ween these disorders in terms of predominant
clinical symptoms, haemodynamic profiles, and
therapeutic response to volume expansion or aug-
menting peripheral vasoconstriction with mido-
drine.45 The possibility of using the HIS and FRAS
to distinguish the cardiovascular reactivity of CFS
from that of other functional somatic syndromes,
such as fibromyalgia20 and neurally-mediated
syncope, suggests that a CFS-characteristic dysauto-
nomia may exist. 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. The observation
that 45% of patients with generalized anxiety
disorder were found to have comparable HIS
values to CFS patients lends support to the
recognized association between generalized anxi-
ety disorder and CFS.2 Our study did not approach
the mechanisms of dysautonomia in the different
groups of patients. The idea that cardiovascular
reactivity is the outcome of arterial baroreflexes is
simplistic, and no longer tenable. Serotonin, adeno-
sine and opioids are additional triggers of the
Betzold-Jarisch reflex, peripheral sympathetic affer-
ents are directly activated by circulating mediators,
and higher nervous centres modulate the cardio-
vascular reflexes.46,47 Investigation of the elaborate
mechanisms involved in particular phenotypes of
cardiovascular reactivity was beyond the aims of
our study.
In clinical practice, the HIS can reinforce the
diagnosis of CFS by providing objective criteria
for the assessment of CFS, which until now,
could only be subjectively inferred. Thus, a HIS
)!0.98 may support the diagnosis of CFS, pro-
viding certain confounding conditions are excluded.
As a general rule, patients with other active medi-
cal or psychiatric conditions should not be diag-
nosed with CFS.1,2 From the clinical point of
view, differentiation of these disorders from CFS
is usually simple. Pathologically elevated HIS
may be expected to occur in cardiovascular
deconditioning following prolonged bed rest or
under zero-gravity,48 in autonomic dysfunction
associated with neurological or chronic inflamma-
tory disorders49,50 or as result of drug effects on the
autonomic nervous system, though no systematic
studies have appraised the effects of any of these
conditions on the HIS. The HIS does not, unfor-
tunately, assist in the challenging differential
diagnosis between CFS and generalized anxiety
disorder.
140 J.E. Naschitz et al.
There are limitations to our study. First, the HIS
was established and tested in patients with mild to
moderate forms of CFS, but not in subjects who
were debilitated or bedridden. Second, the HIS
could only be processed in patients who were
able to complete 30 min of tilt. When orthostatic
symptoms occurred and precluded termination of
the tilt, the score became unsuitable. The lack of
blinding of the technicians who performed the
HUTT to the patients’ diagnoses might have
potentially increased their inclination to interrupt
the tilt if symptoms occurred in CFS patients.
However, dropout rates in patient groups with
CFS, non-CFS fatigue, syncope and anxiety disorder
were similar, thus this form of bias is unlikely. As
calculation of the HIS depends on completion of the
HUTT, it cannot be ascertained or assumed that
those with syncope would have had a HIS )!0.98.
Only the use of other methodologies, not dependant
on completion of the HUTT, could tell us whether
cardiovascular reactivity differs between CFS patients
with syncope and those without. Third, the differ-
ence between diagnosing CFS by CDC criteria
alone1 or based on combined, CDC and HIS criteria
is unclear. No available test can definitely establish
the diagnosis of CFS and serve as gold standard to
assess a hierarchy among surrogate measures such
as HIS and the 37 kDa protein.22 The possibility of
targeting treatment of CFS at normalizing auto-
nomic nervous function and using the HIS as a
measure of the response to treatment, supports the
role of HIS in clinical practice. Prospective studies
may answer this question.
As a practical tool, the HUTT is easily adminis-
tered, its use is not restricted by cultural constraints,
and it is applicable to a wide range of populations.
While performing a HUTT is time-consuming, the
calculation of HIS is speedy. There are many acces-
sible and reasonably priced computer programs that
can perform a fractal analysis. A dedicated software
package for calculation of the HIS is being
developed at our institution, and will be made
available through the Internet.
Elaboration of the FRAS, which recognized the
specific cardiovascular reactivity in CFS by using a
short and well-tolerated tilt phase, may increase the
applicability of this method. Future investigations
may show whether application of the FRAS to the
study of cardiovascular reactivity in CFS reveals
similar reactivity in CFS patients who can and those
who cannot complete a 30-min tilt.
In conclusion, there exists a particular dysauto-
nomia in CFS that differs from dysautonomia in
several other disorders. This distinct abnormality is
described by HIS )!0.98. Therefore, HIS may be
used in the appropriate clinical context to support
the diagnosis of CFS, which until now, could only
be subjectively inferred.
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Appendix: Sources of error and measures to avoid inaccuracies in processing

the HIS

Mental or physical stress, caffeine, Physician certified in the BP measurement techni-

que according to American Heart Association
smoking, medications recommendations
No medications for at least two weeks before the ‘Last supine BP’ is the median of three consecutive
HUTT measurements before tilt
Restriction from smoking and caffeine ingestion for Measurements may be inaccurate in the presence of
6h arrhythmia
Testing from 0800 to 1100 h
Laboratory and equipment shown to patient prior to
the start of the test
Quiet environment and constant room temperature
of 22–25 8C Calibration of the computer programs
No conversation during the HUTT
Calm and attentive examiners SNN1 and Benoit 1.3
Construct 0–change BP and HR data (place
BP measurement with the mercury identical BP values throughout the HUTT).
The FDSL (fractal dimension of a straight line)
sphygmomanometer should measure 1.077
Automatic BP measurement devices not used for If different FDSL values are obtained, reinstall the
assessment of the HIS, due to inaccuracies program