Source: Monthly Journal of the Association of Physicians (QJM)
Preprint
Date: September 19, 2008
URL: http://qjmed.oxfordjournals.org/cgi/content/full/hcn123v1
Postural orthostatic tachycardia syndrome is an under-recognized condition in
chronic fatigue syndrome
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A. Hoad(1), G. Spickett(1), J. Elliott(2) and J. Newton(3,*)
1 Northern CFS/ME Clinical Network, Equinox House, Silver Fox Way, Cobalt
Business Park, Newcastle upon Tyne,
2 ME NorthEast, Bullion Hall, County Durham, and
3 Falls and Syncope Service, Institute of Cellular Medicine, Newcastle
University, Newcastle, UK
* Address correspondence to Prof. J. Newton, Professor of Ageing and Medicine,
Falls and Syncope Service, Institute of Cellular Medicine, Newcastle
University, Newcastle NE1 4LP. Email: julia.newton@nuth.nhs.uk
Received 1 July 2008 and in revised form 27 August 2008
Summary
Background
It has been suggested that postural orthostatic tachycardia syndrome (POTS)
be considered in the differential diagnosis of those with chronic fatigue
syndrome/myalgic encephalomyelitis (CFS/ME). Currently, measurement of
haemodynamic response to standing is not recommended in the UK NICE CFS/ME
guidelines.
Objectives
To determine prevalence of POTS in patients with CFS/ME.
Design
Observational cohort study.
Methods
Fifty-nine patients with CFS/ME (Fukuda criteria) and 52 age- and sex-matched
controls underwent formal autonomic assessment in the cardiovascular
laboratory with continuous heart rate and beat-to-beat blood pressure
measurement (Task Force, CNSystems, Graz Austria). Haemodynamic responses to
standing over 2 min were measured. POTS was defined as symptoms of
orthostatic intolerance associated with an increase in heart rate from the
supine to upright position of >30 beats per minute or to a heart rate of >120
beats per minute on standing.
Results: Maximum heart rate on standing was
significantly higher in the CFS/ME group compared with controls (106 p/m 20
vs. 98 p/m 13; P=0.02). Of the CFS/ME group, 27% (16/59) had POTS compared
with 9% (5) in the control population (P=0.006). This difference was
predominantly related to the increased proportion of those in the CFS/ME
group whose heart rate increased to >120 beats per minute on standing
(P=0.0002). Increasing fatigue was associated with increase in heart rate
(P=0.04; r^2=0.1).
Conclusions
POTS is a frequent finding in patients with CFS/ME. We suggest that clinical evaluation of patients with CFS/ME should include response to standing.
Studies are needed to determine the optimum intervention strategy to manage
POTS in those with CFS/ME.
Introduction
Epidemiological studies suggest that in the United Kingdom 0.2-2% of the
population is affected by chronic fatigue syndrome/myalgic encephalomyelitis
(CFS/ME) that accounts for 1% of all primary care consultations.1 CFS/ME
affects all ages and can profoundly influence a sufferer's ability to
function on a daily basis, work or attend school. Despite its impact on the
population, the cause of CFS/ME remains unknown and there are no effective
pharmacological treatments.
Studies show that fatigue is experienced by almost 50% of those with postural
orthostatic tachycardia syndrome (POTS)2 and it has been suggested that the
presence of POTS should be considered in the differential diagnosis of all
patients diagnosed with CFS/ME.3,4 However, evaluation for POTS is not
considered a routine part of the clinical evaluation of those with CFS/ME and
the recently published UK NICE CFS/ME guidelines do not recommend measurement
of haemodynamic responses to standing in the assessment of those diagnosed
with CFS/ME.5
We therefore examined the prevalence of POTS in a cohort of those with
CFS/ME. To do this, responses to standing were examined in a large series of
subjects with CFS/ME compared with controls.
Methods
Subjects
Subjects with CFS/ME (Fukuda Criteria6) were identified via the patient
support group 'ME North East'. Subjects had been diagnosed with CFS/ME in a
specialist CFS/ME service within 2 years of assessment in the autonomic
laboratory. Controls were recruited via notices placed within the hospital.
Both patients and controls were excluded if taking any medication that could
influence assessment of haemodynamics (e.g. beta-blockers, calcium
antagonists, anti-depressants). Subjects were excluded if not in sinus
rhythm, unable to stand or unable to attend the autonomic laboratory for
assessment. The study was reviewed and approved by the Newcastle and North
Tyneside Local Research Ethics Committee. All patients and controls provided
written informed consent.
Symptom assessment tools
Subjects and controls completed on the day of assessment, a measure of
fatigue impact [Fatigue Impact Scale (FIS)]. The FIS is a 40-item
symptom-specific profile measure of health-related quality of life, commonly
used in medical conditions in which fatigue is a prominent symptom. The scale
allows patients to rate each item on a scale of 0-4, with 0 representing no
problem and 4 representing an extreme problem. Individual scores are summed
to provide a total score with higher scores indicating worse fatigue. This
tool has been validated for self-completion (i.e. assesses a patient's
perceived level and impact of fatigue) in both CFS/ME and normal
populations.7,8
Assessment of haemodynamic responses to standing
Subjects underwent formal autonomic assessment in the cardiovascular
laboratory. All subjects refrained from smoking and caffeine ingestion on the
day of investigation and ate a light breakfast only. All investigations were
performed at the same time of day, and took place in a warm, quiet room. All
cardiovascular assessments were carried out with continuous heart rate and
beat-to-beat blood pressure measurement (Task Force, CNSystems). Heart rate
and blood pressure responses to standing over 2 min were measured.9 Data were
digitized and stored for offline analysis by an investigator blinded to the
fatigue status and whether data was from patients or controls. Baseline
measurements were taken as an average for 20 beats in supine position
immediately prior to standing. Orthostatic heart rate change was the change
in mean heart rate from baseline on standing. The absolute maximum heart rate
on standing was also recorded.
POTS was diagnosed using recognized diagnostic criteria10 and was defined as
symptoms of orthostatic intolerance associated with an increase in heart rate
from the supine to upright position of >30 beats per minute (beat to beat) or
to a heart rate of >120 beats per minute on immediatestanding or during the
2 min of standing.
Statistical analysis
All variables were parametric and therefore comparisons between groups and
correlations were therefore made using the appropriate statistical tests. For
continuous variables, comparisons were made using un-paired t-tests, whilst
for categorical data comparisons were made using Fisher's exact test. Results
are presented throughout as mean p/m SD.
Results
Subjects
Sixty-three subjects with CFS/ME were identified via the patient support
group 'ME North East'. One patient was found not to be in sinus rhythm, two
patients were unable to stand without support, and one subject was too unwell
to attend the autonomic laboratory for assessment. The study cohort therefore
comprised 59 patients with CFS/ME (Fukuda criteria). Mean age of the CFS/ME
group was 47 p/m 12 years with 41 (69%) females. This group was compared with
a group of 52 controls matched group-wise for age and sex [mean age 50 p/m 13
years; P=0.3; 34 (66%) females]. Predictably the CFS/ME group were
significantly more fatigued compared with the control population (assessed
using the FIS; 96 p/m 28 vs. 13 p/m 21, P<0.00001).
Haemodynamic responses to standing in CFS/ME compared with controls
Although mean blood pressure responses to standing were lower in those with
CFS/ME compared with controls none of these parameters reached statistical
significance (Table 1).
When considering heart rate responses to standing, despite a baseline heart
rate that was not significantly different between the CFS/ME group and
controls (84 p/m 17 vs. 80 p/m 14; P=0.2) the maximum heart rate attained
on standing was however significantly higher in the CFS/ME group compared
with controls (106 p/m 20 vs. 98 p/m 13; P=0.02) (Figure 1).
Prevalence of POTS in the CFS/ME group compared with controls
When the diagnostic criteria for POTS were applied to both the CFS/ME and
control groups, 27% (16/59) of the CFS/ME group were found to have POTS,
which was significantly higher than the 9% (5) found in the control
population (Figure 2). This difference was predominantly related to the
increased proportion of those in the CFS/ME group whose heart rate increased
to above 120 beats per minute on standing.
There were no significant differences in fatigue severity, age or sex between
those found to have POTS compared with those CFS/ME patients who did not have
POTS (data not shown).
Increasing fatigue was associated with the increase in heart rate 30 s after
standing (Figure 3).
Discussion
This study describes for the first time, the prevalence of POTS in a cohort
of patients with the clinical diagnosis of CFS/ME. POTS is a frequent finding
in our patients with CFS/ME and we would therefore suggest that the clinical
evaluation of patients presenting with CFS/ME should include heart rate
responses to standing. The prevalence of POTS may in fact be even higher in
this patient group than that reported here, as we limited our observations of
haemodynamics to 2 min of standing. Studies are needed in order to determine
whether the prevalence may be even higher if monitoring is continued for
longer periods.
Symptoms on standing are a frequently described symptom in those with fatigue
in general11,12 and CFS/ME in particular1221 and the physiological
mechanisms that lead to these symptoms are poorly understood. The
pathophysiology of POTS remains unclear, and includes autonomic
abnormalities, hypovolaemia or low blood volume. Furthermore, whether
management of POTS by normalization of heart rate, leads to improvements in
fatigue and the other symptoms of CFS/ME requires further study. We would
suggest, however, that our finding that higher levels of perceived fatigue
were associated with the degree to which heart rate increases on standing,
would imply that this offers potential opportunities for intervention. It is
currently unclear whether POTS is a separate clinical entity distinct from
CFS/ME or whether POTS is a particular subset of CFS/ME where a specific
group of symptoms are particularly marked. Longitudinal clinical studies are
needed in order to define this further. In the meantime, optimizing the
management of those with POTS is critical. The largest series of patients in
the literature confirm a significant symptom burden in those with POTS
including weakness, muscle aches and pains.2 In view of these findings and
without evidence to the contrary, we would strongly suggest that current
medication regimes for the management of POTS are simply symptomatic and need
to be combined with the multifaceted effective interventions performed within
the context of the CFS/ME clinical networks, thus incorporating into POTS
management the other effective components of a fatigue management programme.5
Studies are proposed within our group to compare the efficacy in POTS
patients of medication alone compared with medication with conventional
CFS/ME management.
Interestingly, our CFS/ME with POTS group differed from the demographic group
reported in the largest series of POTS patients to date. In the Mayo series,2
86.8% were females whilst in our group this was lower at 69%, and our group
did include 31% who were over the age of 50 years (mean age in the Mayo
series was 30 years). In the Mayo series, only 48% of those with POTS
experienced fatigue and a wide range of other symptoms, so it may be that
there are a variety of different POTS phenotypes, one (or more) or which
manifest as the symptom of fatigue. An alternative explanation for the
demographic differences between the two groups is related to referral bias.
Studies in adolescents suggest that POTS physiology underlies orthostatic
intolerance in the majority of those with CFS.3 Studies suggest that POTS is
accompanied with a range of autonomic nervous system abnormalities including
vagal withdrawal and enhanced sympathetic modulation, associated with
findings consistent with pooling in the lower limbs, similar
pathophysiological mechanisms as those hypothesized in a proportion of those
with the diagnosis of CFS/ME.12-14
Our clinical impression is that treatment to reduce the heart rate in POTS is
associated with improvements in fatigue.22 This needs to be formally
evaluated in randomized controlled trials in patients with CFS with a POTS
phenotype.
We would suggest that the diagnosis of POTS (a potentially treatable
condition) may be being missed in those attending services with CFS. Studies
suggest that on follow-up, 80% of those with POTS will improve, 60% are
functionally normal and 90% were able to return to work.23,24 It is therefore
important that this diagnosis is considered in all patients presenting with
fatigue and that appropriate investigations performed. We would suggest that
at the very minimum this includes haemodynamic assessment in response to
standing of patients attending CFS/ME clinical services.
Acknowledgements
We are grateful to ME Northeast for their participation.
Funding
ME Research UK; the Local CFS/ME Clinical Network.
Conflict of interest: None declared.
Figure Captions
Figure 1. Maximum heart rate (HR) attained on standing was significantly
higher in the CFS/ME group compared with controls. Results are
presented as mean p/m SD.
Figure 2. The proportion of the CFS/ME group (black bars) compared with
controls (clear bars) who were found to have POTS.
Figure 3. Increasing fatigue (FIS) was associated with the increase in
heart rate (HR) 30s after standing, in those with CFS/ME.
Table
Table 1 Systolic blood pressure (SBP, mmHg) responses in the CFS/ME
group compared with matched controls
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CFS/ME Controls P
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Baseline SBP 130 p/m 18 131 p/m 21 0.7
Nadir SBP 112 p/m 22 114 p/m 24 0.7
Change in SBP 18 p/m 11 17 p/m 11 0.8
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(c) 2008 Oxford University Press
(c) 2008 Association of Physicians
* * *
See also the Cheney on Cardiology article on www.DFWCFIDS.com
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