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ME/CFS Blood Volume Pots

ME/CFS Blood Volume Pots

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05/21/2012

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The head-up tilt test with haemodynamic instability scorein 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 
1
Rheumatology, 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 chronicfatigue syndrome (CFS), we have developed amethod that uses a head-up tilt test (HUTT) toestimate BP and HR instability during tilt, expressedas a ‘haemodynamic instability score’ (HIS).
Aim:
To assess HIS sensitivity and specificity in thediagnosis of CFS.
Design:
Prospective controlled study.
Methods:
Patients with CFS (
=
40), non-CFSchronic fatigue (
=
73), fibromyalgia (
=
41),neurally mediated syncope (
=
58), generalizedanxiety disorder (
=
28), familial Mediterraneanfever (
=
50), arterial hypertension (
=
28), andhealthy subjects (
=
59) were evaluated with astandardized head-up tilt test (HUTT). The HIS wascalculated from blood pressure (BP) and heart rate(HR) changes during the HUTT.
Results:
The tilt was prematurely terminated in22
%
of CFS patients when postural symptomsoccurred and the HIS could not be calculated. Inthe remainder, the median(IQR) HIS values were:CFS
q
2.14(4.67), non-CFS fatigue
À
3.98(5.35),fibromyalgia
À
2.81(2.62), syncope
À
3.7(4.36),generalized anxiety disorder
À
0.21(6.05), healthycontrols
À
2.66(3.14), FMF
À
5.09(6.41), hyperten-sives
À
5.35(2.74) (
-
0.0001 vs. CFS in all groups,except for anxiety disorder,
=
NS). The sensitivityfor CFS at HIS
)
À
0.98 cut-off was 90.3
%
and theoverall specificity was 84.5
%
.
Discussion:
There is a particular dysautonomiain CFS that differs from dysautonomia in otherdisorders, characterized by HIS
)
À
0.98. TheHIS can reinforce the clinician’s diagnosis byproviding objective criteria for the assessment of CFS, which until now, could only be subjectivelyinferred.
Introduction
Clinically evaluated, medically unexplained fatigueof at least 6 months duration, that is of new onset, isnot a result of ongoing exertion, not substantiallyalleviated by rest, and that substantially reducesprevious levels of activity, is called chronic fatiguesyndrome (CFS).
1
Other prominent features of thesyndrome are chronic and recurrent low-gradefever, pharyngitis, lymphadenopathy, arthralgiaand neuropsychological symptoms. The prevalenceof CFS is 0.07–0.2
%
of the population.
2
Theaetiology and pathogenesis of CFS are poorlyunderstood.Previous studies have documented a closeconnection between impairment of autonomicfunctions, 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, Haifa31048, PO Box 4940, Israel. e-mail: Naschitz@tx.technion.ac.il 
Q J Med 
2003;
96
:133–142doi:10.1093/qjmed/hcg018
ß
Association of Physicians 2003
Q J Med 
2003;
96
:133–142doi:10.1093/qjmed/hcg018
 
resonance imaging
9
and single-photon emissiontomography,
10
as well as disruption of thehypothalamic-pituitary-adrenal axis and sero-toninergic and noradrenergic pathways have beendemonstrated,
11,12
and a ‘distal dysautonomiahas been described in CFS patients.
13
As the fast response of the blood pressure (BP)and heart rate (HR) to acute stimuli is underautonomic nervous control, BP and HR measure-ments during orthostatic challenge can be used asone measure of cardiovascular autonomic activity.For this purpose, the head-up tilt test (HUTT) isused. Classical pathological reactions to the HUTTare: vasodepressor reaction, cardioinhibitory reac-tion, orthostatic hypotension and postural tachy-cardia syndrome. In studies using these outcomemeasures, evidence for abnormal cardiovascularreactivity was found in one half of CFS patients. Thelatter measures are non-specific, however, and alsooccur in a variety of disorders unrelated to CFS.
3–8
HR variability during the HUTT is another measureof cardiovascular reactivity in CFS.
14,15
As with theclassical outcomes of the HUTT, abnormalities of HR variability in CFS are not specific for thisdisorder.
16,17
A third method, recently proposed forthe study of the cardiovascular reactivity of CFSpatients involves computing BP and HR changesduring the course of a HUTT, followed by proces-sing the data by image analysis methods. These datareceive numerical expression as the ‘haemo-dynamic instability score’ (HIS). In our previousstudy,
18,19
the best cut-off differentiating CFS fromhealthy patients was HIS
À
0.98. HIS values above
À
0.98 were associated with CFS (sensitivity 97
%
,specificity 96.6
%
). In a second study, we appliedthe proposed HIS threshold of 
À
0.98 to studypopulations which served as ‘test groups’.
19
In the‘test groups’, similarly to the earlier ‘traininggroups’, the HIS threshold of 
À
0.98 differentiatedbetween CFS patients (HIS
=
q
2.02, SD 4.07) andhealthy subjects (HIS
=
À
2.48, SD 4.07).
19
HISvalues higher than
À
0.98 were usually associatedwith CFS.
18–20
The diagnosis of CFS rests largely on patienthistory. In any illness defined by a group of symptoms, two questions arise: do the patients infact report the symptoms that investigators say theyshould, and do those symptoms distinguish patientswith CFS from other fatiguing illnesses?
2
Twostudies have validated the CFS questionnaires: thesymptoms of CFS, but not the control symptoms, aremuch more frequently reported by patients withCFS than by patients with other diseases whichproduce fatigue.
21,22
However, the differentiation of CFS from the other functional somatic syndromes,fibromyalgia and myofascial pain syndrome, maybe 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 tostrengthen the diagnosis of CFS.
3,4
Two develop-ments might advance the diagnosis of CFS. The firstis based on a recent study showing that 72
%
of subjects in a group of patients with CFS hadincreased plasma levels of an abnormal 37 kDaprotein.
24
The possible application of this findingfor diagnostic purposes has not been appraised. Thesecond development is evaluation of dysautonomiaas a possible marker of CFS. A diagnostic role forthe HUTT classical endpoints, as well as for spectralanalysis of HR and BP variability in patients withCFS, has not been defined,
2,8,16,17
although wehave previously suggested that the HIS may beuseful in confirming the diagnosis of CFS.
18–20
Inthe present study, we reassessed the sensitivity of HIS
)
À
0.98 for the diagnosis of CFS in a newgroup of CFS patients. The reproducibility of the HISon repeated examinations was evaluated. Speci-ficity for the diagnosis of CFS was evaluated incomparison with controls, some exhibiting sharedclinical features with CFS (patients with non-CFSchronic fatigue, fibromyalgia, generalized anxietydisorder, neurally mediated syncope) and others notsuffering from fatigue (patients with FamilialMediterranean Fever, essential hypertension, healthysubjects).
Methods
All participants gave informed consent, and ourinstitution’s committee for human research app-roved the study. All patients were fully ambulatoryat the time of the study. The patients were not takingmedications for at least 2 weeks before the study.Technicians carrying out the HUTT were informedas to the patients’ diagnosis, but did not know of theintention to compare between the groups. Data of earlier studies, which used somewhat differentequations and were based upon slightly differentdependent measures
18,20,25
were revised, expandedand processed according to the latest equation.
18
Patients
CFS patients 
(
=
40) were consecutive subjectsreferred from a CFS clinic for evaluation with theHUTT. All patients met the Centers of DiseaseControl and Prevention definition
1
of CFS, had noother diagnosable medical or psychiatric illness toexplain their symptoms, and did not have fibro-myalgia (FM), based on a specific tender pointscount
-
11/18.
26
The subjects’ median age was 27
134
J.E. Naschitz 
et al.134
J.E. Naschitz 
et al.
 
years (range 20–71 years) and the M:F ratio was12:28. The median duration of illness was 16.7months (range 7 months to 4 years). All patients hadmoderate fatigue at rest and severe fatigue withexertion. The patients’ mean fatigue impact score
27
was 69.1 (SD 12.8). The fatigue impact scoreexamines the patients’ perception of the functionallimitations that fatigue has caused over severalmonths. Subjects are asked to rate the extent towhich fatigue has caused problems for them inrelation to exemplar statements, and each item isquantified on a scale of 0-3: 0, no problem to 3,extreme problem. The fatigue impact score includesthree subscales to assess perceived fatigue impacton cognitive functioning (10 items), physical func-tioning (10 items), and psychosocial functioning (20items). The maximum score is 120. Healthy personsscore
-
20.
Patients with non-CFS chronic fatigu
(
=
73)were consecutive subjects referred from a CFSclinic. Similarly to the CFS patients, they com-plained of fatigue of new onset,
28
not a result of ongoing exertion, not substantially alleviated byrest, associated with substantial reduction in pre-vious levels of activity, and lasting 3 months ormore, but they did not otherwise meet the definitioncriteria of CFS. The subjects’ median age was 38years (range 19–65 years) and the M:F ratio was24:49. Median duration of illness was 7 months(range 3–13 months). The patients’ mean fatigueimpact score was 69.3 (SD 10.2).
Syncope patients 
(
=
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 previous3 months. Patients with co-morbidities, inclusiveCFS were excluded. Fifteen subjects reportedchronic fatigue. The subjectsmedian age was24 years (range 18–48 years) and the M:F ratiowas 18:40. The diagnosis of neurally mediatedsyncope
29
was eventually established.
Fibromyalgia (FM) patients 
(
=
41) were referredfrom a rheumatology clinic. The diagnosis of FMwas based on criteria of the American College of Rheumatology for FM.
26
Sixteen subjects who alsoreported fatigue but did not meet the diagnosis of CFS were included. The patients’ median age was30 years (range 22–67) and the M:F ratio was 13:28.
Generalized anxiety disorder patients 
(30)(
=
28) were referred from a psychiatry clinic.They had a history of palpitation and atypical chestpain, but no symptoms consistent with CFS, FM orother co-morbidities. The patients’ mean age was31.4 years (SD 8.8) and 75
%
patients were women.
Familial Mediterranean Fever (FMF) patients 
(
=
50) were referred from an adult rheumatologyclinic. The patients had recovered from the lastattack of FMF
31
at least 14 days before the HUTT.Patients with co-morbidities were excluded. Thepatients’ median age was 30 years (range 21–60years) and the M:F ratio was 25:25.
Essential hypertension (HT) patients 
(
=
28)included subjects with mild to moderate systolicand diastolic hypertension (HT) according tocriteria of the Sixth Joint National Committee onDetection, Evaluation and Treatment of High BloodPressure.
32
Patients had normal chest X-rays andelectrocardiograms. Their median age was 29 years(range 18–49 years) and the M:F ratio was 9:19.
Healthy control subjects 
(
=
59) were physiciansand paramedics working on the medical ward, whovolunteered to participate in the study. Subjectswere eligible if they did not report persistent fatigueor syncope during the preceding 12 months, andhad normal findings on physical examination,routine laboratory tests, chest X-rays, and electro-cardiogram. Their median age was 27 years (range23–54 years) and the M:F ratio was 31:28.The patient age was significantly higher in thenon-CFS group compared to all other groups(
-
0.01). Male predominance in the group of healthy subjects was statistically significant only incomparison to the CFS patients group (
-
0.05).
Computation of the haemodynamicinstability score (HIS)
The protocol of the HUTT was based on the 10-minsupine/30-min head-up tilt test as previouslydescribed.
18
Testing was conducted from 0800 hto 1100 h, in a quiet environment, and at constantroom temperature of 22–25
8
C. The patients main-tained a regular meal schedule, but were restrictedfrom smoking and caffeine ingestion for 6 h prior tothe examination. Intake of food products andmedications with sympathomimetic activity priorto the study was prohibited.Manual BP readings were taken by a physiciancertified in the BP measurement techniqueaccording to American Heart Association recom-mendations.
33
We favoured the mercury columnsphygmomanometer (Baumanometer, standbymodel 0661–0250), since this is the standard non-invasive method for BP measurement, and is themost accurate for evaluation of BP at rest
34
andduring HUTT.
35
The HR measurements wererecorded on an electrocardiographic monitor. Thepatient lay in a supine position on the tilt table,secured to the table at the chest, hips and kneeswith adhesive girdles. The cuff of the BP recordingdevice was attached to the left arm, which was
Diagnosing CFS 
135
Diagnosing CFS 
135

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