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The prevalence of symptomatic orthostatic hypotension in patients with Parkinson’s disease and atypical parkinsonism
Parkinsonism and Related Disorders 17 (2011) 625e628
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
The prevalence of symptomatic orthostatic hypotension in patients with Parkinson’s disease and atypical parkinsonism Ainhi D. Ha, Caitlin H. Brown, Michele K. York, Joseph Jankovic* Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 March 2011 Received in revised form 23 May 2011 Accepted 25 May 2011
Non-motor symptoms in Parkinson disease (PD) have been increasingly recognized as a major cause of declining health-related quality of life. We aimed to determine the prevalence of symptomatic orthostatic hypotension (OH) in patients with PD and atypical parkinsonism, and to evaluate the risk factors for OH in this population. We reviewed the records of 1318 patients diagnosed with PD or atypical parkinsonism at the Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine. The frequency of symptomatic OH was 81% (21/26) in patients with multiple system atrophy (MSA), 18% (198/1125) of PD patients, and 19% (31/167) of patients with non-MSA atypical parkinsonism. Among PD patients, those with symptoms of OH were significantly older (p ¼ 0.001), had more advanced Hoehn & Yahr stage (p ¼ 0.007), a longer duration of PD symptoms (p ¼ 0.031), and a greater range between their highest and lowest sitting systolic and diastolic BPs (p ¼ 0.0001) over time. In the atypical parkinsonism group, excluding MSA, patients with symptoms of OH were taking more anti-hypertensive medications than those without symptoms of OH (p ¼ 0.043). On the other hand, MSA patients with symptoms of OH were less likely to be taking anti-hypertensive medications than those without symptoms (p ¼ 0.035). In conclusion, symptomatic OH is a common cause of disability in patients with PD, atypical parkinsonian disorders, and especially in patients with MSA. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Hypotension Orthostatic Parkinson disease Atypical parkinsonism Multiple system atrophy
1. Introduction Orthostatic lightheadedness associated with orthostatic hypotension (OH) is one of many symptoms that occur in patients with Parkinson’s disease (PD) as a result of autonomic dysfunction [1]. Dysautonomia may herald the onset of PD even before motor symptoms manifest and, along with other non-motor features, may gradually and seriously impact the HRQOL [2,3]. In the Sydney Multicenter Study of 136 patients with PD, after 20 years of follow-up, 48% of the survivors had symptomatic orthostatic hypotension and 87% experienced falls, some of which could have resulted from OH [4]. Indeed, the presence of OH in patients with PD has been associated with increased postural sway [5] and falls [6]. Previous estimates of the prevalence of PD have varied considerably [7e9]. We aimed to determine the
* Corresponding author. Director of Parkinson’s Disease Center, and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030, USA. Tel.: þ1 713 798 5998; fax: þ1 713 798 6808. E-mail address: [email protected] (J. Jankovic). URL: http://www.jankovic.org/ 1353-8020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2011.05.020
prevalence of symptomatic OH in patients with PD and atypical parkinsonism, and evaluate risk factors for symptomatic hypotension in this population. 2. Methods We reviewed the medical records of all patients who attended the Parkinson’s Disease Center and Movement Disorders Clinic (PDCMDC) at Baylor College of Medicine between October 2009 and October 2010 with a diagnosis of PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), vascular parkinsonism (VP), and “other causes” of atypical parkinsonism. The records were examined for orthostatic symptoms; those that appeared following assumption of an erect posture, and resolving in the recumbent position. These symptoms included lightheadeness, dizziness, fatigue, weakness and blurred vision. We also recorded blood pressure (BP) readings, taken routinely in a sitting position at the beginning of each clinic visit. We noted the highest and lowest reading that was documented in the medical records and then calculated the “systolic blood pressure range” and “diastolic blood pressure range” for each patient, which we defined as the difference between the highest and lowest recorded sitting systolic and diastolic blood pressures, respectively, during their attendance at our clinic. Orthostatic hypotension was defined as a documented 20 mm Hg drop in systolic blood pressure or a 10 mm Hg drop in diastolic blood pressure between supine (or sitting) and standing positions. In addition, we recorded demographic data including age, gender, duration of PD symptoms, Hoehn & Yahr (H&Y) stage, and relevant co-morbidities such as the presence of hypertension, diabetes mellitus (DM), and cardiovascular risk factors. We also recorded anti-hypertensive medication use, including quantity and class of
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A.D. Ha et al. / Parkinsonism and Related Disorders 17 (2011) 625e628
medication. Specifically, we included angiotensin converting enzyme (ACE) inhibitors, angiotension receptor antagonists, beta blockers, calcium channel antagonists, nitrates, alpha antagonists, and diuretics. We noted the use of medications used to treat orthostatic hypotension, including midodrine, fludrocortisione, and the investigational drug L-threo-3,4-dihydroxyphenylserine (Droxidopa) [1,10,11]. Total daily levodopa equivalent doses were calculated for each patient, based on recent guidelines [12]. Ordinal and categorical data, such as H&Y, absence or presence of diabetes, number of anti-hypertensive medications and gender, were analyzed using Chisquare analysis. Continuous variables including age, duration of PD, total daily levodopa equivalent dose and blood pressure range, were analyzed using the ManneWhitney U test. We compared the variables between patients with OH and without OH within the categories of PD and atypical Parkinsonism. Within the atypical Parkinsonism group, the variables were also compared between patients with MSA and non-MSA atypical Parkinsonism. For the PD group, logistic regression analysis was conducted to determine the strength of the relationships between the variables that were significant on univariate analysis and OH membership. Logistic regression analysis was not completed within the atypical parkinsonism and MSA groups because our initial analysis did not uncover statistical significance amongst multiple variables.
3. Results There were 1318 patients with PD (n ¼ 1,125, 85.4%) or atypical parkinsonism (n ¼ 193, 14.6%) seen at PDCMDC between October 2009 and October 2010. This included 292 new patients, and 1026 established patients. The established patients had a mean duration of follow-up of 4.1 years (range: 1 month to 26 years). The average time interval between follow-up appointments for each patient was 5.9 months (range: 1 month to 29 months). BP range was calculated in 88.2% of PD patients and 74.6% of atypical PD patients. New patients had only one BP recorded and, therefore, BP range could not be calculated. Patients with PD were, on average, 4 years younger than those with atypical parkinsonism and were symptomatic for 2 years longer (Table 1). Of all PD patients, 198/1125 (17.6%) had symptoms of OH, but only 115/1125 (10.2%) had documented supine and standing BP. There were 4 patients who fulfilled the diagnostic criteria for OH, but were asymptomatic. Of the 193 patients with atypical parkinsonism, 52 (26.9%) had symptoms of OH, with 13 patients having documented BP changes that met the criteria for OH. The frequency of symptomatic OH in patients with MSA was 80.7% (21/26). In contrast, the frequency of OH in non-MSA cases ranged from 7.1% to 31.3% (Table 2). Collectively, symptoms of OH were found in 18.6% (31/167) of non-MSA atypical parkinsonism cases. We found that PD patients with symptoms of OH were significantly older (p ¼ 0.0001), had more advanced H&Y stage (p ¼ 0.007), a longer duration of PD symptoms (p ¼ 0.031), a wider range between their highest and lowest recorded sitting diastolic BPs (p ¼ 0.0001) and a wider range between their highest and lowest recorded sitting systolic BPs (p ¼ 0.0001) than those without symptoms of OH. Gender, the presence or absence of DM, total daily
Table 2 Prevalence of symptomatic OH within each diagnostic category. Diagnosis (N)
Symptomatic OH (%)
No symptomatic OH (%)
Idiopathic PD (1125) MSA (26) DLB (32) VP (38) Other (57) PSP (26) CBD (14)
18 81 31 26 12 11 7
82 19 69 74 88 89 93
levodopa equivalent dose and the number of anti-hypertensive medications used were not significantly different between the PD patients with and without OH. Logistic regression analysis revealed that systolic BP range was the strongest predictor for symptomatic OH in PD patients, above and beyond that of duration, H&Y, levodopa equivalents, diastolic BP range and age (Wald ¼ 18.7, p ¼ 0.0001, Exp(B) ¼ 1.02). To evaluate if the length of follow-up time influenced the variability in the BP range variable, we used length of follow-up at our clinic as a covariate in a univariate analysis with BP range. The presence of symptomatic OH remained significantly associated with BP range independent of the influence of length of follow-up (F ¼ 54.8, p ¼ 0.053). In the non-MSA atypical parkinsonism group, patients with symptoms of OH were taking more anti-hypertensive medications than those without symptoms of OH (p ¼ 0.043). On the other hand, MSA patients with symptoms of OH were less likely to be taking anti-hypertensive medications than those without symptoms of OH (p ¼ 0.035). In both non-MSA atypical parkinsonism and MSA, age, gender, duration of PD symptoms, H&Y staging, presence of DM, total daily levodopa equivalent dose, and systolic and diastolic BP range were comparable between patients with and without OH. Logistic regression analysis was not performed within the non-MSA atypical parkinsonism and MSA groups because multiple variables were not found to be significant. 4. Discussion The current study is one of the largest to date to examine the prevalence and risk factors of OH in PD and atypical parkinsonism. We found that symptoms of OH are frequent among parkinsonian patients attending a specialized clinic, present in 18% of PD patients, 19% of patients with non-MSA atypical parkinsonism, and in 81% of patients with MSA. Among PD patients, older age, more advanced disease, longer duration of PD symptoms, and a widely ranging sitting BP were associated with increased risk of symptomatic OH. Our findings are consistent with the published estimates of OH in PD ranging between 14% and 47% [7e9] with the frequency
Table 1 Demographic data in patients with PD, non-MSA atypical parkinsonism, and MSA. Within each group, comparisons are shown between patients with and without symptomatic orthostatic hypotension. Demographics
PD (n ¼ 1125) [mean [SD] or n(%)]
Atypical Parkinsonism w/o MSA (n ¼ 167) [mean [SD] or n(%)]
MSA (n ¼ 26) [mean [SD] or n(%)]
OH
No OH
p value
OH
No OH
p value
OH
No OH
p value
Gender (% male) Age (years) Duration (months) H&Y (1e5) Levodopa (daily mg) Diabetes mellitus (% positive) #Antihypertensives (0e4) Systolic range (mmHg) Diastolic range (mmHg)
67.2% 71.1 (10.3) 135.2 (81.9) 2.61 (0.8853) 847.6 (479.8) 7.87% 0.75 (0.991) 37.5 (24.4) 15.7 (14.6)
61.4% 67.2 (31.3) 127.7 (94.9) 2.39 (0.859) 878.8 (547.2) 10.7% 0.73 (0.974) 26.3 (16.5) 10.9 (8.9)
0.127 0.0001 0.031 0.007 0.678 0.200 0.998 0.0001 0.0001
58.1% 75.4 (9.28) 98.8 (61.3) 3.02 (1.08) 738.7 (505.3) 12.9% 1.16 (1.44) 27.6 (17.8) 10.9 (7.08)
59.6% 76.6 (48.8) 102.3 (102.3) 2.90 (1.07) 618.3 (506.4) 13.9% 0.94 (1.02) 23.9 (18.2) 9.68 (7.83)
0.879 0.087 0.594 0.767 0.202 0.876 0.043 0.336 0.263
52.4% 62.8 (7.11) 80.43 (55.7) 3.50 (1.26) 1063.1 (948.5) 16.7% 0.14 (0.359) 31.4 (33.2) 22.4 (22.4)
20.0% 60.6 (13.7) 93.0 (79.6) 2.80 (1.30) 926.0 (658.5) 0.00% 0.800 (0.837) 19.3 (5.03) 6.67 (6.51)
0.192 0.396 0.870 0.560 1.000 0.619 0.035 0.763 0.063
A.D. Ha et al. / Parkinsonism and Related Disorders 17 (2011) 625e628
increasing to 48% of patients with advanced PD [4]. The overall prevalence of OH has been reported to be as high as 58.2% in one study [13]. Although the number of anti-hypertensive medications increases the risk of OH in the elderly population [14], this finding was not present in our study of PD patients. Furthermore, we did not find an association between symptomatic OH and total daily levodopa equivalent dose or the presence of diabetes mellitus. The finding of an association between greater sitting systolic and diastolic blood pressure variation and the presence of symptomatic OH is a previously unreported finding in PD. The discrepancies in prevalence and associated risk factors may be related to several factors, including patient selection, the criteria used to define OH, and the method of BP measurement [5]. For example, not all studies have adhered to the strict definition: a 20 mm Hg systolic or 10 mm Hg diastolic BP fall within 3 min of tilting or standing [15]. Although non-motor symptoms in PD are often underreported, they have been increasingly recognized as a major source of poor HRQOL [2,3]. Autonomic symptoms are a common non-motor manifestation in PD, and may include disturbances in cardiovascular, uro-genital, gastrointestinal, sudomotor, sleep, and respiratory function [1,16]. Autonomic symptom severity is associated with more motor dysfunction, depressive symptoms, cognitive dysfunction, psychiatric complications, nighttime sleep disturbances, and excessive daytime sleepiness [17]. Symptoms of OH are the most commonly reported manifestation of cardiovascular disturbance in PD [18]. Autonomic symptoms, particularly OH, seem to be more common in the postural-instability-gaitdifficulty form of PD rather than the tremor-dominant variety [19]. In addition to postural sway [5] and increased risk of falls [6], OH has been linked to stroke, cognitive decline [20] and increased mortality [21]. In our study, a larger range between the highest and lowest recorded sitting systolic BP was the most significant predictor for symptoms of OH in the PD group (p ¼ 0.0001). We did consider whether this wide range in systolic BP occurred by chance, as a function of having more BP recordings in a patient who has a longer duration of follow-up, and therefore more advanced disease. To address this issue, we analyzed the length of attendance at our center as a covariate with systolic blood pressure range. We found that, independent of duration of follow-up, a greater systolic BP range was still associated with the presence of symptomatic OH. Thus, this new finding suggests that the autonomic dysfunction underlying OH may also be reflected by greater systolic blood pressure variation, as measured repeatedly by sitting BP readings. Few studies have examined the prevalence of OH in patients with atypical parkinsonism. The PRIAMO study reported the occurrence of symptoms due to OH in MSA to be 54.6% [9]. The frequency of postural symptoms in other atypical Parkinsonian syndromes varied from 0 in CBD, 13.3% in PSP, 18.3% in VP, to 21.4% in DLB. It is interesting to note that the relative frequencies of symptomatic hypotension between each category of atypical parkinsonism was similar in our study and the PRIAMO study. Although the small sample sizes limit definitive conclusions, both studies found that the frequencies of OH symptoms increased in the following ascending order: CBD < PSP < VP < DLB < MSA. The high frequency of symptomatic OH in MSA is not unexpected, in view of the established occurrence of automonic failure in this condition. We found the prevalence of symptomatic OH in DLB to be 31.3%. Autonomic dysfunction is a well-documented feature of Lewy Body diseases, in which noradrenergic post-ganglionic sympathetic denervation may be seen [22]. Interestingly, MSA patients with symptoms of OH were less likely to be taking anti-hypertensive medications than PD patients with OH. This is probably due to discontinuation of anti-hypertensive medication early in the course of MSA in order to minimize symptoms of OH.
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Cardiovascular autonomic disturbance in PD is probably related to both centrally and peripherally mediated mechanisms. Several studies have provided evidence that OH in PD is due to failure of reflexive sympathetically mediated cardiovascular stimulation from sympathetic denervation [22,23]. Heart rate variability has also shown to be decreased [24], and may suggest parallel cardiac parasympathetic dysfunction [25]. PD patients demonstrate evidence of reflexive sympathetic neurocirculatory failure and extracardiac noradrenergic denervation [26]. Those patients with OH have been found to have a lower orthostatic increment in plasma norepinephrine compared to those without OH. PD patients with OH, off dopaminergic medication, also had lower plasma norepinephrine during supine rest than control subjects [26]. In addition, Lewy bodies have been found in the peripheral and central nervous system, including the autonomic pathways [18]. A 30e40% reduction in neurons has been reported in the intermediolateral nucleus at the levels of the upper and lower thoracic segments of PD patients compared to controls [27]. The majority of patients in the current study with documented orthostatic hypotension were symptomatic, in keeping with previous studies showing high specificity of postural symptoms for OH [15]. We do acknowledge however, that this finding is likely to be biased, as patients with symptoms of OH were more likely to undergo additional orthostatic BP testing after reporting symptoms. In addition, the retrospective nature of the study meant that the accuracy of our data is reliant on the completeness of documentation in the medical records. It is certainly possible that some patients were not asked specifically about OH, or that these findings were not recorded. In addition, the lack of complete orthostatic blood pressure data in our study limited further evaluation of asymptomatic cases. As such, the total prevalence of OH would have almost certainly been underestimated. A previous study found that 20% of PD patients with OH did not report symptoms [15]. The definition of OH, according to the Consensus Committee of the American Autonomic Society and the American Academy of Neurology denotes a reduction of blood pressure within 3 min of standing or with the use of a tilt table in the head-up position [28]. One study however, demonstrated that OH might still occur after the currently recommended duration of 3 min [15]. In addition, OH was found to occur more often after tilting than standing, suggesting that use of the current recommendations may still result in an underestimation the true frequency of OH. Nonetheless, more comprehensive data regarding routine assessment of orthostatic blood pressures would have been valuable in this study. The presence of postural symptoms including dizziness, lightheadedness, weakness and fatigue, although presumed to be due to orthostatic hypotension, may have also been related to a variety of other etiologies. Further assessment for other cause of dizziness, lightheadedness and other presyncopal symptoms, including other neurological and cardiovascular causes, would be useful. Despite these limitations, our data revealed consistent trends and associations with symptomatic OH in a large population of patients with PD and atypical parkinsonism. Symptoms of OH occur in 81% of patients with MSA, a four-fold higher frequency than the observed prevalence in PD and atypical parkinsonian population. Older age, more advanced and longer-duration disease, and the previously unreported finding of greater BP variation are associated with symptomatic OH in PD. Symptomatic OH was associated with a greater number of anti-hypertensive medications in the non-MSA atypical parkinsonism group. MSA patients with symptoms of OH were less likely to be taking anti-hypertensive medications than those without symptoms. Recognition and management of this common condition, and other non-motor symptoms, is important in the care of patients with PD and atypical parkinsonism.
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Acknowledgments Statistical analysis performed by Dr. Michele York. References [1] Mostile G, Jankovic J. Treatment of dysautonomia associated with Parkinson’s disease. Parkinsonism Relat Disord 2009 Dec;15(Suppl. 3):S224e32. [2] Gallagher DA, Lees AJ, Schrag A. What are the most important nonmotor symptoms in patients with Parkinson’s disease and are we missing them? Mov Disord 2010 Nov 15;25(15):2493e500. [3] Politis M, Wu K, Molloy S, P GB, Chaudhuri KR, Piccini P. Parkinson’s disease symptoms: the patient’s perspective. Mov Disord 2010 Aug 15;25(11): 1646e51. [4] Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 2008 Apr 30;23(6):837e44. [5] Matinolli M, Korpelainen JT, Korpelainen R, Sotaniemi KA, Myllyla VV. Orthostatic hypotension, balance and falls in Parkinson’s disease. Mov Disord 2009 Apr 15;24(5):745e51. [6] Kerr GK, Worringham CJ, Cole MH, Lacherez PF, Wood JM, Silburn PA. Predictors of future falls in Parkinson disease. Neurology 2010 Jul 13;75(2):116e24. [7] Bonuccelli U, Lucetti C, Del Dotto P, Ceravolo R, Gambaccini G, Bernardini S, et al. Orthostatic hypotension in de novo Parkinson disease. Arch Neurol 2003 Oct;60(10):1400e4. [8] Allcock LM, Ullyart K, Kenny RA, Burn DJ. Frequency of orthostatic hypotension in a community based cohort of patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 2004 Oct;75(10):1470e1. [9] Colosimo C, Morgante L, Antonini A, Barone P, Avarello TP, Bottacchi E, et al. Non-motor symptoms in atypical and secondary parkinsonism: the PRIAMO study. J Neurol 2010 Jan;257(1):5e14. [10] Kaufmann H. L-dihydroxyphenylserine (Droxidopa): a new therapy for neurogenic orthostatic hypotension: the US experience. Clin Auton Res 2008 Mar;18(Suppl. 1):19e24. [11] Mathias CJ. L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience. Clin Auton Res 2008 Mar;18(Suppl. 1):25e9. [12] Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord 2010 Nov 15;25(15):2649e53. [13] Senard JM, Rai S, Lapeyre-Mestre M, Brefel C, Rascol O, Rascol A, et al. Prevalence of orthostatic hypotension in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997 Nov;63(5):584e9.
[14] Low PA. Prevalence of orthostatic hypotension. Clin Auton Res 2008 Mar; 18(Suppl. 1):8e13. [15] Jamnadas-Khoda J, Koshy S, Mathias CJ, Muthane UB, Ragothaman M, Dodaballapur SK. Are current recommendations to diagnose orthostatic hypotension in Parkinson’s disease satisfactory? Mov Disord 2009 Sep 15; 24(12):1747e51. [16] Mehanna R, Jankovic J. Respiratory problems in neurologic movement disorders. Parkinsonism Relat Disord 2010 Dec;16(10):628e38. [17] Verbaan D, Marinus J, Visser M, van Rooden SM, Stiggelbout AM, van Hilten JJ. Patient-reported autonomic symptoms in Parkinson disease. Neurology 2007 Jul 24;69(4):333e41. [18] Jain S. Multi-organ autonomic dysfunction in Parkinson disease. Parkinsonism Relat Disord 2011 Feb;17(2):77e83. [19] Allcock LM, Kenny RA, Burn DJ. Clinical phenotype of subjects with Parkinson’s disease and orthostatic hypotension: autonomic symptom and demographic comparison. Mov Disord 2006 Nov;21(11):1851e5. [20] Rose KM, Couper D, Eigenbrodt ML, Mosley TH, Sharrett AR, Gottesman RF. Orthostatic hypotension and cognitive function: the Atherosclerosis risk in Communities study. Neuroepidemiology 2010;34(1):1e7. [21] Rose KM, Eigenbrodt ML, Biga RL, Couper DJ, Light KC, Sharrett AR, et al. Orthostatic hypotension predicts mortality in middle-aged adults: the Atherosclerosis Risk In Communities (ARIC) Study. Circulation 2006 Aug 15; 114(7):630e6. [22] Rascol O, Schelosky L. 123I-metaiodobenzylguanidine scintigraphy in Parkinson’s disease and related disorders. Mov Disord 2009;24(Suppl. 2): S732e41. [23] Goldstein DS, Holmes CS, Dendi R, Bruce SR, Li ST. Orthostatic hypotension from sympathetic denervation in Parkinson’s disease. Neurology 2002 Apr 23; 58(8):1247e55. [24] Mihci E, Kardelen F, Dora B, Balkan S. Orthostatic heart rate variability analysis in idiopathic Parkinson’s disease. Acta Neurol Scand 2006 May;113(5): 288e93. [25] Shibata M, Morita Y, Shimizu T, Takahashi K, Suzuki N. Cardiac parasympathetic dysfunction concurrent with cardiac sympathetic denervation in Parkinson’s disease. J Neurol Sci 2009 Jan 15;276(1e2):79e83. [26] Goldstein DS, Eldadah BA, Holmes C, Pechnik S, Moak J, Saleem A, et al. Neurocirculatory abnormalities in Parkinson disease with orthostatic hypotension: independence from levodopa treatment. Hypertension 2005 Dec; 46(6):1333e9. [27] Wakabayashi K, Takahashi H. The intermediolateral nucleus and Clarke’s column in Parkinson’s disease. Acta Neuropathol 1997 Sep;94(3):287e9. [28] The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology 1996 May;46(5):1470.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
The prevalence of symptomatic orthostatic hypotension in patients with Parkinson’s disease and atypical parkinsonism Ainhi D. Ha, Caitlin H. Brown, Michele K. York, Joseph Jankovic* Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 March 2011 Received in revised form 23 May 2011 Accepted 25 May 2011
Non-motor symptoms in Parkinson disease (PD) have been increasingly recognized as a major cause of declining health-related quality of life. We aimed to determine the prevalence of symptomatic orthostatic hypotension (OH) in patients with PD and atypical parkinsonism, and to evaluate the risk factors for OH in this population. We reviewed the records of 1318 patients diagnosed with PD or atypical parkinsonism at the Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine. The frequency of symptomatic OH was 81% (21/26) in patients with multiple system atrophy (MSA), 18% (198/1125) of PD patients, and 19% (31/167) of patients with non-MSA atypical parkinsonism. Among PD patients, those with symptoms of OH were significantly older (p ¼ 0.001), had more advanced Hoehn & Yahr stage (p ¼ 0.007), a longer duration of PD symptoms (p ¼ 0.031), and a greater range between their highest and lowest sitting systolic and diastolic BPs (p ¼ 0.0001) over time. In the atypical parkinsonism group, excluding MSA, patients with symptoms of OH were taking more anti-hypertensive medications than those without symptoms of OH (p ¼ 0.043). On the other hand, MSA patients with symptoms of OH were less likely to be taking anti-hypertensive medications than those without symptoms (p ¼ 0.035). In conclusion, symptomatic OH is a common cause of disability in patients with PD, atypical parkinsonian disorders, and especially in patients with MSA. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Hypotension Orthostatic Parkinson disease Atypical parkinsonism Multiple system atrophy
1. Introduction Orthostatic lightheadedness associated with orthostatic hypotension (OH) is one of many symptoms that occur in patients with Parkinson’s disease (PD) as a result of autonomic dysfunction [1]. Dysautonomia may herald the onset of PD even before motor symptoms manifest and, along with other non-motor features, may gradually and seriously impact the HRQOL [2,3]. In the Sydney Multicenter Study of 136 patients with PD, after 20 years of follow-up, 48% of the survivors had symptomatic orthostatic hypotension and 87% experienced falls, some of which could have resulted from OH [4]. Indeed, the presence of OH in patients with PD has been associated with increased postural sway [5] and falls [6]. Previous estimates of the prevalence of PD have varied considerably [7e9]. We aimed to determine the
* Corresponding author. Director of Parkinson’s Disease Center, and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030, USA. Tel.: þ1 713 798 5998; fax: þ1 713 798 6808. E-mail address: [email protected] (J. Jankovic). URL: http://www.jankovic.org/ 1353-8020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2011.05.020
prevalence of symptomatic OH in patients with PD and atypical parkinsonism, and evaluate risk factors for symptomatic hypotension in this population. 2. Methods We reviewed the medical records of all patients who attended the Parkinson’s Disease Center and Movement Disorders Clinic (PDCMDC) at Baylor College of Medicine between October 2009 and October 2010 with a diagnosis of PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), vascular parkinsonism (VP), and “other causes” of atypical parkinsonism. The records were examined for orthostatic symptoms; those that appeared following assumption of an erect posture, and resolving in the recumbent position. These symptoms included lightheadeness, dizziness, fatigue, weakness and blurred vision. We also recorded blood pressure (BP) readings, taken routinely in a sitting position at the beginning of each clinic visit. We noted the highest and lowest reading that was documented in the medical records and then calculated the “systolic blood pressure range” and “diastolic blood pressure range” for each patient, which we defined as the difference between the highest and lowest recorded sitting systolic and diastolic blood pressures, respectively, during their attendance at our clinic. Orthostatic hypotension was defined as a documented 20 mm Hg drop in systolic blood pressure or a 10 mm Hg drop in diastolic blood pressure between supine (or sitting) and standing positions. In addition, we recorded demographic data including age, gender, duration of PD symptoms, Hoehn & Yahr (H&Y) stage, and relevant co-morbidities such as the presence of hypertension, diabetes mellitus (DM), and cardiovascular risk factors. We also recorded anti-hypertensive medication use, including quantity and class of
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A.D. Ha et al. / Parkinsonism and Related Disorders 17 (2011) 625e628
medication. Specifically, we included angiotensin converting enzyme (ACE) inhibitors, angiotension receptor antagonists, beta blockers, calcium channel antagonists, nitrates, alpha antagonists, and diuretics. We noted the use of medications used to treat orthostatic hypotension, including midodrine, fludrocortisione, and the investigational drug L-threo-3,4-dihydroxyphenylserine (Droxidopa) [1,10,11]. Total daily levodopa equivalent doses were calculated for each patient, based on recent guidelines [12]. Ordinal and categorical data, such as H&Y, absence or presence of diabetes, number of anti-hypertensive medications and gender, were analyzed using Chisquare analysis. Continuous variables including age, duration of PD, total daily levodopa equivalent dose and blood pressure range, were analyzed using the ManneWhitney U test. We compared the variables between patients with OH and without OH within the categories of PD and atypical Parkinsonism. Within the atypical Parkinsonism group, the variables were also compared between patients with MSA and non-MSA atypical Parkinsonism. For the PD group, logistic regression analysis was conducted to determine the strength of the relationships between the variables that were significant on univariate analysis and OH membership. Logistic regression analysis was not completed within the atypical parkinsonism and MSA groups because our initial analysis did not uncover statistical significance amongst multiple variables.
3. Results There were 1318 patients with PD (n ¼ 1,125, 85.4%) or atypical parkinsonism (n ¼ 193, 14.6%) seen at PDCMDC between October 2009 and October 2010. This included 292 new patients, and 1026 established patients. The established patients had a mean duration of follow-up of 4.1 years (range: 1 month to 26 years). The average time interval between follow-up appointments for each patient was 5.9 months (range: 1 month to 29 months). BP range was calculated in 88.2% of PD patients and 74.6% of atypical PD patients. New patients had only one BP recorded and, therefore, BP range could not be calculated. Patients with PD were, on average, 4 years younger than those with atypical parkinsonism and were symptomatic for 2 years longer (Table 1). Of all PD patients, 198/1125 (17.6%) had symptoms of OH, but only 115/1125 (10.2%) had documented supine and standing BP. There were 4 patients who fulfilled the diagnostic criteria for OH, but were asymptomatic. Of the 193 patients with atypical parkinsonism, 52 (26.9%) had symptoms of OH, with 13 patients having documented BP changes that met the criteria for OH. The frequency of symptomatic OH in patients with MSA was 80.7% (21/26). In contrast, the frequency of OH in non-MSA cases ranged from 7.1% to 31.3% (Table 2). Collectively, symptoms of OH were found in 18.6% (31/167) of non-MSA atypical parkinsonism cases. We found that PD patients with symptoms of OH were significantly older (p ¼ 0.0001), had more advanced H&Y stage (p ¼ 0.007), a longer duration of PD symptoms (p ¼ 0.031), a wider range between their highest and lowest recorded sitting diastolic BPs (p ¼ 0.0001) and a wider range between their highest and lowest recorded sitting systolic BPs (p ¼ 0.0001) than those without symptoms of OH. Gender, the presence or absence of DM, total daily
Table 2 Prevalence of symptomatic OH within each diagnostic category. Diagnosis (N)
Symptomatic OH (%)
No symptomatic OH (%)
Idiopathic PD (1125) MSA (26) DLB (32) VP (38) Other (57) PSP (26) CBD (14)
18 81 31 26 12 11 7
82 19 69 74 88 89 93
levodopa equivalent dose and the number of anti-hypertensive medications used were not significantly different between the PD patients with and without OH. Logistic regression analysis revealed that systolic BP range was the strongest predictor for symptomatic OH in PD patients, above and beyond that of duration, H&Y, levodopa equivalents, diastolic BP range and age (Wald ¼ 18.7, p ¼ 0.0001, Exp(B) ¼ 1.02). To evaluate if the length of follow-up time influenced the variability in the BP range variable, we used length of follow-up at our clinic as a covariate in a univariate analysis with BP range. The presence of symptomatic OH remained significantly associated with BP range independent of the influence of length of follow-up (F ¼ 54.8, p ¼ 0.053). In the non-MSA atypical parkinsonism group, patients with symptoms of OH were taking more anti-hypertensive medications than those without symptoms of OH (p ¼ 0.043). On the other hand, MSA patients with symptoms of OH were less likely to be taking anti-hypertensive medications than those without symptoms of OH (p ¼ 0.035). In both non-MSA atypical parkinsonism and MSA, age, gender, duration of PD symptoms, H&Y staging, presence of DM, total daily levodopa equivalent dose, and systolic and diastolic BP range were comparable between patients with and without OH. Logistic regression analysis was not performed within the non-MSA atypical parkinsonism and MSA groups because multiple variables were not found to be significant. 4. Discussion The current study is one of the largest to date to examine the prevalence and risk factors of OH in PD and atypical parkinsonism. We found that symptoms of OH are frequent among parkinsonian patients attending a specialized clinic, present in 18% of PD patients, 19% of patients with non-MSA atypical parkinsonism, and in 81% of patients with MSA. Among PD patients, older age, more advanced disease, longer duration of PD symptoms, and a widely ranging sitting BP were associated with increased risk of symptomatic OH. Our findings are consistent with the published estimates of OH in PD ranging between 14% and 47% [7e9] with the frequency
Table 1 Demographic data in patients with PD, non-MSA atypical parkinsonism, and MSA. Within each group, comparisons are shown between patients with and without symptomatic orthostatic hypotension. Demographics
PD (n ¼ 1125) [mean [SD] or n(%)]
Atypical Parkinsonism w/o MSA (n ¼ 167) [mean [SD] or n(%)]
MSA (n ¼ 26) [mean [SD] or n(%)]
OH
No OH
p value
OH
No OH
p value
OH
No OH
p value
Gender (% male) Age (years) Duration (months) H&Y (1e5) Levodopa (daily mg) Diabetes mellitus (% positive) #Antihypertensives (0e4) Systolic range (mmHg) Diastolic range (mmHg)
67.2% 71.1 (10.3) 135.2 (81.9) 2.61 (0.8853) 847.6 (479.8) 7.87% 0.75 (0.991) 37.5 (24.4) 15.7 (14.6)
61.4% 67.2 (31.3) 127.7 (94.9) 2.39 (0.859) 878.8 (547.2) 10.7% 0.73 (0.974) 26.3 (16.5) 10.9 (8.9)
0.127 0.0001 0.031 0.007 0.678 0.200 0.998 0.0001 0.0001
58.1% 75.4 (9.28) 98.8 (61.3) 3.02 (1.08) 738.7 (505.3) 12.9% 1.16 (1.44) 27.6 (17.8) 10.9 (7.08)
59.6% 76.6 (48.8) 102.3 (102.3) 2.90 (1.07) 618.3 (506.4) 13.9% 0.94 (1.02) 23.9 (18.2) 9.68 (7.83)
0.879 0.087 0.594 0.767 0.202 0.876 0.043 0.336 0.263
52.4% 62.8 (7.11) 80.43 (55.7) 3.50 (1.26) 1063.1 (948.5) 16.7% 0.14 (0.359) 31.4 (33.2) 22.4 (22.4)
20.0% 60.6 (13.7) 93.0 (79.6) 2.80 (1.30) 926.0 (658.5) 0.00% 0.800 (0.837) 19.3 (5.03) 6.67 (6.51)
0.192 0.396 0.870 0.560 1.000 0.619 0.035 0.763 0.063
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increasing to 48% of patients with advanced PD [4]. The overall prevalence of OH has been reported to be as high as 58.2% in one study [13]. Although the number of anti-hypertensive medications increases the risk of OH in the elderly population [14], this finding was not present in our study of PD patients. Furthermore, we did not find an association between symptomatic OH and total daily levodopa equivalent dose or the presence of diabetes mellitus. The finding of an association between greater sitting systolic and diastolic blood pressure variation and the presence of symptomatic OH is a previously unreported finding in PD. The discrepancies in prevalence and associated risk factors may be related to several factors, including patient selection, the criteria used to define OH, and the method of BP measurement [5]. For example, not all studies have adhered to the strict definition: a 20 mm Hg systolic or 10 mm Hg diastolic BP fall within 3 min of tilting or standing [15]. Although non-motor symptoms in PD are often underreported, they have been increasingly recognized as a major source of poor HRQOL [2,3]. Autonomic symptoms are a common non-motor manifestation in PD, and may include disturbances in cardiovascular, uro-genital, gastrointestinal, sudomotor, sleep, and respiratory function [1,16]. Autonomic symptom severity is associated with more motor dysfunction, depressive symptoms, cognitive dysfunction, psychiatric complications, nighttime sleep disturbances, and excessive daytime sleepiness [17]. Symptoms of OH are the most commonly reported manifestation of cardiovascular disturbance in PD [18]. Autonomic symptoms, particularly OH, seem to be more common in the postural-instability-gaitdifficulty form of PD rather than the tremor-dominant variety [19]. In addition to postural sway [5] and increased risk of falls [6], OH has been linked to stroke, cognitive decline [20] and increased mortality [21]. In our study, a larger range between the highest and lowest recorded sitting systolic BP was the most significant predictor for symptoms of OH in the PD group (p ¼ 0.0001). We did consider whether this wide range in systolic BP occurred by chance, as a function of having more BP recordings in a patient who has a longer duration of follow-up, and therefore more advanced disease. To address this issue, we analyzed the length of attendance at our center as a covariate with systolic blood pressure range. We found that, independent of duration of follow-up, a greater systolic BP range was still associated with the presence of symptomatic OH. Thus, this new finding suggests that the autonomic dysfunction underlying OH may also be reflected by greater systolic blood pressure variation, as measured repeatedly by sitting BP readings. Few studies have examined the prevalence of OH in patients with atypical parkinsonism. The PRIAMO study reported the occurrence of symptoms due to OH in MSA to be 54.6% [9]. The frequency of postural symptoms in other atypical Parkinsonian syndromes varied from 0 in CBD, 13.3% in PSP, 18.3% in VP, to 21.4% in DLB. It is interesting to note that the relative frequencies of symptomatic hypotension between each category of atypical parkinsonism was similar in our study and the PRIAMO study. Although the small sample sizes limit definitive conclusions, both studies found that the frequencies of OH symptoms increased in the following ascending order: CBD < PSP < VP < DLB < MSA. The high frequency of symptomatic OH in MSA is not unexpected, in view of the established occurrence of automonic failure in this condition. We found the prevalence of symptomatic OH in DLB to be 31.3%. Autonomic dysfunction is a well-documented feature of Lewy Body diseases, in which noradrenergic post-ganglionic sympathetic denervation may be seen [22]. Interestingly, MSA patients with symptoms of OH were less likely to be taking anti-hypertensive medications than PD patients with OH. This is probably due to discontinuation of anti-hypertensive medication early in the course of MSA in order to minimize symptoms of OH.
627
Cardiovascular autonomic disturbance in PD is probably related to both centrally and peripherally mediated mechanisms. Several studies have provided evidence that OH in PD is due to failure of reflexive sympathetically mediated cardiovascular stimulation from sympathetic denervation [22,23]. Heart rate variability has also shown to be decreased [24], and may suggest parallel cardiac parasympathetic dysfunction [25]. PD patients demonstrate evidence of reflexive sympathetic neurocirculatory failure and extracardiac noradrenergic denervation [26]. Those patients with OH have been found to have a lower orthostatic increment in plasma norepinephrine compared to those without OH. PD patients with OH, off dopaminergic medication, also had lower plasma norepinephrine during supine rest than control subjects [26]. In addition, Lewy bodies have been found in the peripheral and central nervous system, including the autonomic pathways [18]. A 30e40% reduction in neurons has been reported in the intermediolateral nucleus at the levels of the upper and lower thoracic segments of PD patients compared to controls [27]. The majority of patients in the current study with documented orthostatic hypotension were symptomatic, in keeping with previous studies showing high specificity of postural symptoms for OH [15]. We do acknowledge however, that this finding is likely to be biased, as patients with symptoms of OH were more likely to undergo additional orthostatic BP testing after reporting symptoms. In addition, the retrospective nature of the study meant that the accuracy of our data is reliant on the completeness of documentation in the medical records. It is certainly possible that some patients were not asked specifically about OH, or that these findings were not recorded. In addition, the lack of complete orthostatic blood pressure data in our study limited further evaluation of asymptomatic cases. As such, the total prevalence of OH would have almost certainly been underestimated. A previous study found that 20% of PD patients with OH did not report symptoms [15]. The definition of OH, according to the Consensus Committee of the American Autonomic Society and the American Academy of Neurology denotes a reduction of blood pressure within 3 min of standing or with the use of a tilt table in the head-up position [28]. One study however, demonstrated that OH might still occur after the currently recommended duration of 3 min [15]. In addition, OH was found to occur more often after tilting than standing, suggesting that use of the current recommendations may still result in an underestimation the true frequency of OH. Nonetheless, more comprehensive data regarding routine assessment of orthostatic blood pressures would have been valuable in this study. The presence of postural symptoms including dizziness, lightheadedness, weakness and fatigue, although presumed to be due to orthostatic hypotension, may have also been related to a variety of other etiologies. Further assessment for other cause of dizziness, lightheadedness and other presyncopal symptoms, including other neurological and cardiovascular causes, would be useful. Despite these limitations, our data revealed consistent trends and associations with symptomatic OH in a large population of patients with PD and atypical parkinsonism. Symptoms of OH occur in 81% of patients with MSA, a four-fold higher frequency than the observed prevalence in PD and atypical parkinsonian population. Older age, more advanced and longer-duration disease, and the previously unreported finding of greater BP variation are associated with symptomatic OH in PD. Symptomatic OH was associated with a greater number of anti-hypertensive medications in the non-MSA atypical parkinsonism group. MSA patients with symptoms of OH were less likely to be taking anti-hypertensive medications than those without symptoms. Recognition and management of this common condition, and other non-motor symptoms, is important in the care of patients with PD and atypical parkinsonism.
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