J Neurol (2013) 260:1752–1756
DOI 10.1007/s00415-013-6859-5
ORIGINAL COMMUNICATION
Nocturnal hypertension and dysautonomia in patients
with Parkinson’s disease: are they related?
Koldo Berganzo • Begoña Dı́ez-Arrola • Beatriz Tijero • Johanne Somme
Elena Lezcano • Verónica Llorens • Iratxe Ugarriza • Roberto Ciordia •
J. C. Gómez-Esteban • Juan J. Zarranz
Received: 30 October 2012 / Revised: 6 January 2013 / Accepted: 29 January 2013 / Published online: 15 February 2013
Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Orthostatic hypotension and supine hyperten-
sion frequently coexist in Parkinson’s disease (PD)
patients, leading to visceral damage and increased mor-
tality rates. The aim of this paper is to analyze the fre-
quency and association of both conditions in a sample of
outpatients with PD. A total of 111 patients, diagnosed
with PD, were studied. Disease duration, treatment, car-
diovascular risk factors, UPDRS I-IV and Scopa Aut scale
scores were reported. Subjects underwent 24-h ambulatory
blood pressure (BP) monitoring and were assessed for
orthostatic hypotension. We compared our results with
those published in 17,219 patients using the same protocol
and the same type of device. Overall, 71.1 % had no proper
circadian rhythm. This frequency was significantly higher
than that of the control population (48 %). The prevalence
K. Berganzo (&)
B. Tijero
E. Lezcano
I. Ugarriza

R. Ciordia
J. C. Gómez-Esteban
J. J. Zarranz
Autonomic and Movement Disorders Unit, Neurology Service,
Basque Health Service (Osakidetza), Cruces University Hospital,
Plaza de Cruces s/n, Barakaldo 48903, Spain
e-mail: koldo.berganzocorrales@osakidetza.net
K. Berganzo
B. Tijero
E. Lezcano
I. Ugarriza

R. Ciordia
J. C. Gómez-Esteban
J. J. Zarranz
Department of Neurosciences, University of the Basque Country,
Leioa, Spain
B. Dı́ez-Arrola
Biscaye Parkinson’s Disease Society, Bilbao, Spain
J. Somme
Department of Neurology, Alava University Hospital,
Vitoria-Gasteiz, Spain
V. Llorens
Nuclear Medicine Service, Cruces University Hospital,
Barakaldo, Spain
123
•
of the nondipper or riser patterns was higher in patients
with orthostatic hypotension (77.8 vs. 66.7 %). There was a
correlation between nightly increases in diastolic blood
pressure and changes in BP during the orthostatic test.
Patients taking higher doses of treatment had less decreases
in SBP (cc:-0.25; p = 0.007) and DBP (cc:-0.33;
p \ 0.001) at night, however there was no relation with
drug type. The majority of patients with Parkinson’s dis-
ease show an altered circadian rhythm of blood pressure.
Patients with a non-dipper or riser pattern on 24 h ABPM
exhibited a higher prevalence of autonomic disorders
(orthostatic hypotension) and received higher doses of
dopaminergic treatment. A day–night variation in diastolic
blood pressure was the most important marker of these
findings.
Keywords Parkinson disease
Autonomic disorders

Nocturnal hypertension
24-h ambulatory blood pressure
monitoring (ABPM)
Dopaminergic treatment
Introduction
Autonomic nervous system disorders are common in
patients with Parkinson’s disease (PD) [1]. Orthostatic
hypotension and supine hypertension frequently coexist in
the same patient [2]. This produces a change in the circa-
dian rhythm of blood pressure and is an independent car-
diovascular risk factor. These findings often go unnoticed,
and, therefore, do not receive adequate treatment, which
predisposes patients to end-organ damage and plays a role
in the increased mortality of persons with PD [3, 4].
Cardiovascular risk factors, such as diabetes mellitus
and central obesity, have been associated with PD, but
precise data on the relationship between blood pressure and
J Neurol (2013) 260:1752–1756
PD are lacking [5]. Patients with end-stage PD are hospital-
ized frequently for cardiovascular disease (18.5 %), but
rarely for PD (1.0 %). Long-term use of calcium channel
blockers was associated with a significantly reduced risk of a
Parkinson disease diagnosis, while the risk was not substan-
tially altered for users of other antihypertensive drugs [6].
The aim of this paper is to analyze the frequency of
nocturnal hypertension and orthostatic hypotension in a
sample of outpatients with Parkinson’s disease, to study the
association between these two conditions, and ascertain
whether they are related to the presence of heart disease or
other end-organ damage.
Materials and methods
We prospectively studied 111 patients (62 males, mean age
67.80 ± 8.62 years, disease duration 6.59 ± 5.22 years)
(Table 1) diagnosed with PD according to the UK Par-
kinson’s Disease Society Brain Bank criteria. Severity of
Parkinson’s disease was rated according to Hoehn and
Yahr stage: 3 patients were at stage 1 (2.7 %), 14 were at
stage 1.5 (12.6 %), 34 were at stage 2 (30.6 %), 46 were at
stage 2.5 (41.4 %), 12 were at stage 3 (10.8 %) and 2 were
at stage 4 (1.8 %). Participants were recruited consecu-
tively between May 2010 and January 2012 from the
Movement Disorders Unit, Cruces Hospital University and
the Biscay Parkinson’s Disease Association, and were
evaluated and studied by the same group of neurologists
(JCGE, BT and KB). Before inclusion in the study, all
patients provided written informed consent via a form
approved by the local ethics committee.
All patients underwent 24-h ambulatory blood pressure
monitoring (ABPM) according to the MAPAPRES
Table 1 Frequency of cardiovascular risk factors in the patient group
and the prevalence of major complications on target organ
Variable Mean ± SD or N (%)
Gender 62 male (55.9 %),
49 female (44.1 %)
Age 67.80 ± 8.62
Disease duration (years) 6.59 ± 5.22
Hypertension 46 (41.4 %)
Diabetes mellitus 14 (12.6 %)
Hypercholesterolemia 36 (33.4 %)
Antihypertensive therapy 48 (43.2 %)
Anticoagulant therapy 6 (5.4 %)
Stroke 4 (3.6 %)
Ischemic heart disease 8 (7.2 %)
Peripheral arterial disease 2 (1.8 %)
1753
protocol of the Spanish Hypertension Society (SEH-LEL-
HA), and using software from Spacelabs Medical, Inc.
Mean waking and sleeping SBP and DBP were calculated
and the nocturnal BP dip (%) was calculated as (waking
SBP–sleeping SBP)/waking SBP. According to the extent
of their nocturnal BP dip, patients were classified as a
dipper (BP decline between 10 and 20 %), extreme dipper
(dip [20 %), nondipper (dip [0 % but \10 %), or riser
(\0 % change in BP). The burden of hypertension was
estimated using the SEH-LELHA criteria ([135/85 mmHg
during the daytime or activity and [110/70 mmHg at night
or at rest). ABPM was repeated until a valid reading per-
centage above 70 % was achieved. Study participants were
included in the National Registry of the Spanish Hyper-
tension Society (MAPAPRES). This study assessed the
prevalence of hypertension in a large sample of patients
from the general Spanish population. We compared our
results with those published in 17,219 patients using the
same protocol and the same type of device [7].
Baseline BP was measured with the patient supine, after
at least 20 min of rest, and after 3 min of standing
(orthostatic test). We used the following diagnostic criteria
for orthostatic hypotension: in nonhypertensive patients, a
decline of 20 mmHg or more in SBP and/or 10 mmHg or
more in DBP; in hypertensive patients, a decline of more
than 30 mmHg in SBP. We also assessed patients’ mental
status (UPDRS I), activities of daily living (UPDRS II),
motor situation (UPDRS III), dopaminergic drugs and
motor complications (UPDRS IV), as well as the presence
of vascular risk factors, use of antiparkinsonian and anti-
hypertensive agents, body mass index (BMI), and end-
organ damage (heart, kidney, etc.).
Finally, the mean L-Dopa equivalent daily dose (LEDD)
was calculated as shown: 100 mg of L-Dopa: 133 mg sus-
tained release L-Dopa, 75 mg of L-Dopa with entacapone,
5 mg ropirinole, 5 mg rotigotine, 1 mg of pramipexole, 1 mg
pergolide, 1 mg lisuride, 10 mg bromocriptine, and 1 mg of
cabergoline [18].
Statistical analysis
For quantitative variables, data are expressed as means and
standard deviations; qualitative variables are expressed as
proportions. For all quantitative variables, the Kolmogo-
rov–Smirnov test was used to test for normality. Parametric
tests were used for comparison of means (Student’s t test
for independent samples). Time-to-event curves were cal-
culated by the Kaplan–Meier method. Multivariate analysis
of the independent predictors of pathological blood
pressure pattern (nondipper or riser) free survival was
performed using the Cox proportional hazards model.
A two-tailed p value of \0.05 was considered significant.
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Lastly, the Pearson correlation coefficient was used to test Table 2 Summary of the main variables in the ambulatory recording
for correlations between the different variables. of blood pressure and prevalence of orthostatic hypotension
Statistical analyses were carried out using SPSS Version Variable Mean ± SD or N (%)
19 (IBM SPSS, USA).
Valid readings 84.7 ± 16.2
Dipper pattern 26 (23.4 %)
Results Non-dipper pattern 53(47.7 %)
Riser pattern 26(23.4 %)
We obtained a high percentage of successful ABPM Extreme dipper pattern 6 (5.4 %)
readings in 111 patients with Parkinson’s disease (84.7 %). BP, 24 h average (mmHg) SBP 122.9 ± 16.4
The patterns observed were: 26 patients (23.4 %) dippers, 6 DBP 73.8 ± 9.8
(5.4 %) extreme dippers, 53 (47.7 %) nondippers and 26 BP, average waking (mmHg) SBP 124.1 ± 19.8
(23.4 %) had a riser pattern (Table 2). Overall, 71.1 % of DBP 75.6 ± 12.1
patients had no proper physiological circadian rhythm. This BP, average sleeping (mmHg) SBP 118.8/17.7
frequency was significantly higher than that of the control DBP 69.3 ± 10.4
population, where 52.0 % of subjects had a normal circa- Diurnal BP load 34.2 ± 27.2
dian rhythm. There was a greater burden of hypertension Nocturnal BP load 71.3 ± 30.8
during sleep (nocturnal BP load 71.3 ± 30.8; diurnal BP Orthostatic Hypotension 45 (40.5 %)
load 34.2 ± 27.2) (Table 2). Forty-five patients (40.5 %)
had orthostatic hypotension. The prevalence of the non-
dipper or riser patterns was higher in these patients (77.8
vs. 66.7 %; p = 0.2) (Fig. 1). Correlation analysis was
carried out between orthostatic hypotension presence and
cardiovascular items of the SCOPA-AUT scale (ortho-
statism, dizziness and syncope), no significant correlations
were found. There was a correlation between day-night
increases in diastolic blood pressure (diastolic dip on 24 h
ABPM) and changes in diastolic (cc: -0.21; p = 0.03) BP
during autonomic test. No significant differences were
observed between the increase in nocturnal SBP and
decreases in SBP and DBP during autonomic test. Forty-six
patients (41.4 %) were diagnosed with hypertension. On
average, the patients in our study were taking 0.59 ± 0.8
antihypertensive drugs, versus 1.4 ± 1.3 among controls.
There were no significant differences in circadian rhythm
pattern between hypertensive and normotensive patients
(Fig. 1). There was a correlation between years since
diagnosis of PD and nocturnal rises in SBP (cc = 0.25;
p = 0.008) and DBP (cc = 0.27; p = 0.004) on ABPM.
A totally of 17 patients (15.3 %) were in treatment with Fig. 1 Twenty-four hours blood pressure circadian patterns in
agonist monotherapy, 33 patients (29.7 %) received L-dopa patients with and without hypertension and in patients with and
monotherapy and 61 patients (55 %) received combinated without orthostatic hypotension
therapy. The mean totally LEDD was 642.99 ± 349.91 mg.
Patients taking higher doses of treatment had lower decreases nondipping pattern or presence of OH. UPDRS III scores
in SBP (cc:-0.25; p = 0.007) and for DBP (cc:-0.331; were similar across all ABPM patterns (dippers,
p \ 0,001) at night, however there was no relation with drug 27.9 ± 7.3; nondippers, 29.6 ± 8.0; risers, 29.8 ± 7.8;
type (agonist monotherapy, L-dopa monotherapy or combi- non significant). Fifty-five patients (49.5 %) had tremor at
nation therapy). Patients with raiser or non dipping patter rest on physical examination. These patients were more
were taking higher doses of LEDD. likely to have a normal circadian rhythm on ABPM (tre-
Finally, we studied the relationship between motor mor, 34.5 %; no tremor, 23.2 %; p = 0.08) (Fig. 2). There
phenotype (UPDRS III and Hoehn and Yahr) and circadian was no difference in Hoehn and Yahr staging according to
pattern on ABPM. We did not find differences among clinical phenotype (tremor dominant and no tremor domi-
different Hoehn and Yahr staging classification and nant PD).

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J Neurol (2013) 260:1752–1756
Fig. 2 Abnormal 24 h blood pressure circadian pattern-free survival
curves estimated by Cox proportional hazards regression in PD
patients event-free survival curves turn depending on the presence of
tremor dominant phenotype or not tremor dominant phenotype
Discussion
Reversal of the blood pressure circadian rhythms in most
patients with PD is the mayor finding of this study. Overall,
71.1 % of these patients had no proper circadian rhythm.
This frequency was significantly higher than in the control
population, in which 52.0 % of subjects had a normal
circadian rhythm [7], and was also higher than those
reported in other studies of PD patients [4]. Our findings
are not explained by a higher prevalence of arterial
hypertension or by treatment with antihypertensive agents.
Patients with PD, progressive supranuclear palsy, and
multiple-system atrophy frequently exhibit pathological
nocturnal BP regulation (no dip, or even a rise pattern, in
nocturnal BP) as compared with controls [4]. Absence of
the nocturnal BP dip and orthostatic hypotension may
account for the increased cardiovascular mortality of per-
sons with extrapyramidal syndromes [3, 8].
Patients with a nondipper or riser pattern on 24 h ABPM
had a higher prevalence of autonomic disorders [9]. A day–
night variation in diastolic blood pressure was the most
important marker of these findings. In patients with PD and
autonomic failure, nocturnal hypertension leads to natri-
uresis and polyuria, which, in turn, may cause severe
orthostatic hypotension in the morning hours [8, 10]. A
high nocturnal blood pressure load is associated with an
increased prevalence of end-organ damage [11]. In our
study, the presence of ischemic heart disease and cere-
brovascular disease was 10.8 % higher among patients than
1755
in the control group (8 %), despite the higher incidence of
hypertension and higher average body mass index of the
latter [7]. Denervation supersensitivity of the vascular
alpha-adrenergic receptors due to sympathetic denervation
may contribute to supine hypertension [12]. Other poten-
tially involved factors may be defective baroreflex activity,
nocturnal fluid retention, or pharmacotherapy for OH [13].
Approximately 30–40 % of PD patients have OH [14]; on
the basis of these data, one could speculate that loss of the
circadian rhythm of blood pressure is an early sign of
dysautonomia in these patients. An interesting point is that
the patients with higher dose of dopaminergic treatment
showed more inversion in BP circadian rhythm, controlling
for the motor status, age, and time since onset of the dis-
ease. This fact should be take into account in patients with
a high cardiovascular risk or no proper BP circadian
rhythm. L-dopa seems not to have influence on the severity
of orthostatic hypotension and autonomic tests [19], how-
ever this does not seem to be the case with the circadian
pattern of BP.
We found no relationship between UPDRS III scores
and the circadian pattern of blood pressure on ABPM.
However, we did observe a trend toward less circadian
rhythm changes in patients with tremor. Some studies
suggest a close association between cardiac sympathetic
degeneration and bradykinesia, rigidity, age at onset of PD,
and disease duration [15–17].
In conclusion, we have presented the to-date largest
series of ABPM in patients with Parkinson’s disease. Most
patients had pathological changes in the normal circadian
rhythm of blood pressure. Patients with a nondipper or riser
pattern on ABPM had a higher prevalence of autonomic
disorders and higher total LEDD. These pathological BP
patterns were less frequent among patients with tremor at
rest. It is essential that blood pressure disorders be detected
early in this patient population, as they can lead to an
increased frequency of end-organ damage. We suggest that
these issues should be taken into account for the adequate
management of antihypertensive and dopaminergic treat-
ments in patients with PD. Ambulatory blood pressure
monitoring must be performed before treating orthostatic
hypotension with midodrine or other drugs which could get
worse nocturnal hypertension. We believe that prospective
tracing studies should be conducted to assess the real
impact of such inversion in circadian rhythm in patients
with PD.
Acknowledgments Funding: this work was supported by Depart-
ment of Industry of the Basque Government (SAIOTEK
S-DI11BF002).
Conflicts of interest No, there are no competing interests. The
research was funded by Department of Industry of the Basque
Government, but nobody of authors receive financial gain.
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