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Cardiovascular autonomic testing in extrapyramidal disorders
Journal of the Neurological Sciences 310 (2011) 129–132
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Cardiovascular autonomic testing in extrapyramidal disorders Tjalf Ziemssen a, b,⁎, Heinz Reichmann b a b
ANF-lab, Neurological University Clinic, Dresden, Germany Neurological University Clinic, Dresden, Germany
a r t i c l e
i n f o
Article history: Received 9 March 2011 Received and in revised form 28 June 2011 Accepted 19 July 2011 Available online 11 August 2011 Keywords: Parkinson's disease Cardiovascular dysautonomia Orthostatic hypotension Autonomic testing
a b s t r a c t Various diagnostic tests are available to demonstrate autonomic failure in extrapyramidal disease. Autonomic function tests can identify parasympathetic and sympathetic dysfunction. While specialized tests are only available in autonomic labs, routine tests such as 24 h ambulatory blood pressure measurements can be broadly used in clinical practice eg. as screening tests. In this review, we briefly introduce functional cardiovascular autonomic testing and propose a workup plan for patients with extrapyramidal disease. In all patients with extrapyramidal disease, screening for autonomic dysfunction should be performed. In the case of pathological findings, detailed autonomic testing should be considered with repeated measurements at follow up visits. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Recognition of autonomic dysfunction continues to improve, in part aided by advances in non-invasive clinical testing. Especially in extrapyramidal disorders, autonomic symptoms are common but underrated and neglected in terms of treatment [1–3]. The prevalence of dysautonomia in PD varies between 14 and 80% depending on the collective and methodology [4], a subjective impairment of daily life is reported by more than half of PD patients [5]. Especially patients with atypical Parkinsonian syndromes like multiple system atrophy (MSA) usually present early in the disease process with fast progressing dysautonomia. The differentiation between PD with advanced dysautonomia and MSA is challenging and requires the use of sophisticated diagnostic techniques [6,7]. There are no significant differences of autonomic dysfunction between the different MSA subtypes [8]. Even patients with progressive supranuclear palsy (PSP) have been shown to develop autonomic dysfunction to a certain degree [9]. Dysfunction of postganglionic sympathetic efferences is widely regarded as primary cause of dysautonomia in PD while postganglionic lesions are not present in MSA. Unlike PD patients, MSA patients feature pronounced central autonomic abnormalities as do PSP patients [10,12]. In dementia with Levy bodies (DLB), autonomic
dysfunction may result from preganglionic dysfunction in addition to postganglionic dysfunction [11]. Thus, the evaluation of the autonomic function is crucial for diagnosis and treatment at different stages of disease [13]. Dysautonomia commonly occurs more frequently in advanced stages of the disease. It impacts on the subjective picture of the symptoms, the quality of life and renders individual treatment schemes necessary [14,15]. Cardiovascular dysautonomia particularly characterized by orthostatic hypotension has been shown to be a significant independent predictor of mortality [16]. Studies from cardiology and diabetology have shown that the impairment of autonomic reflexes plays an important adverse role. Increased cardiovascular mortality has been reported in patients with different extrapyramidal disorders. The mortality of PD patients is almost doubled compared with that of age and sex-matched healthy controls [17]. In a 20-year follow-up study, Ben-Shlomo and Marmot demonstrated an increase in heart ischemia related deaths which may account for the increased mortality in extrapyramidal disorders [18]. Cardiovascular autonomic dysfunction could be at least partly responsible for the increased cardiac mortality in patients with extrapyramidal disease [19]. Therefore, cardiovascular autonomic testing may be of prognostic/predictive value for cardiovascular mortality in patients with extrapyramidal diseases. 2. Autonomic cardiovascular testing
⁎ Corresponding author at: Autonomes und neuroendokrinologisches Funktionslabor, Klinik und Poliklinik für Neurologie, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, D-01307 Dresden, Germany. Tel.: +49 351 458 3859; fax: +49 351 458 5873. E-mail address: [email protected] (T. Ziemssen). URL: http://www.neuro.med.tu-dresden.de (T. Ziemssen). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.07.032
Unlike other systems, the function of the autonomic nervous system normally cannot be directly assessed. Instead, responses of complex overlapping autonomic reflex loops, most commonly of heart rate and blood pressure, are measured after controlled perturbations of the system. The techniques most widely used in the clinical setting
130
T. Ziemssen, H. Reichmann / Journal of the Neurological Sciences 310 (2011) 129–132
entail the measurement of an end-organ response to a physiological provocation [19]. In this review, these tests of cardiovascular autonomic function will be presented: 3. Heart rate variability (HRV) Heart rate variability during deep metronomic breathing (6 cycles/min) is the most widely used index of cardiovagal parasympathetic function including the expiratory to inspiratory ratio (E:I ratio) (Fig. 1). Other tests that measure parasympathetic cardiovagal functioning include measures of HRV during rest, coughing, diving reflex, standing, squatting, and active lying down. The heart rate (HR) response to the Vasalva manoeuvre is discussed below. While parameters like E:I ratio are considered to be measures in the time domain, HR analysis in the frequency domain is increasingly applied. The power in specific frequency bands correlates to higher frequency respiratory (parasympathetic) or slower midrange primarily adrenergic activity. A ratio of high to low band power produces a “balance” measure of parasympathetic and sympathetic tone. This activity can be monitored at rest and under different cardiovascular conditions. Our group could demonstrate highly prevalent cardiovagal failure in patients with PD, MSA and PSP [8,20]. 4. Valsalva manoeuvre (VM) The Valsalva manoeuvre (VM) is a reliable and reproducible method that provides information regarding parasympathetic and sympathetic function. VM is typically performed by blowing through a mouthpiece connected to a mercury manometer (40 mmHg) for 15 s (Fig. 1). A direct measure of the hemodynamic response to the VM can be obtained with a non-invasive beat-to-beat blood pressure monitor. The decrease in blood pressure during the early phase II, the recovery
of blood pressure in late phase II and the increase in blood pressure during phase IV of the VM serve as measures of vasomotor adrenergic function [21]. The Valsalva ratio (VR) is a measure of cardiovagal functioning which is calculated by dividing the R–R interval of the HR nadir over the HR peak during this period. Normative values of VR are well established and decline with age. VM abnormalities are also highly prevalent in patients with PD, MSA and PSP [8,20,21]. 5. Active or passive orthostasis The most frequently performed cardiovascular test of the sympathetic nervous system function is the blood pressure response to postural change (active standing or passive tilting). Passive tilting on a tilt-table provokes more exaggerated blood pressure responses than active standing since it minimizes the compensatory response resulting from active muscle contraction. Hence, it has been suggested to be more sensitive (Fig. 2). Orthostatic hypotension, the most frequent symptom of cardiovascular autonomic dysfunction [23,24], occurs when the systolic blood pressure decreases at least 20 mm Hg or the diastolic blood pressure at least 10 mm Hg within 3 min of 60° upright tilt or of standing [22]. Orthostatic hypotension can be asymptomatic or symptomatic. Symptoms generally encompass dizziness, weakness, nausea, pain or blurred vision. Roughly 50% of PD patients with advanced disease stages complain about general symptoms of orthostatic hypotension upon standing [25]. 6. 24 h ambulatory blood pressure measurement (ABPM) 24 h ambulatory blood pressure monitoring (ABPM) allows for determination of the circadian blood pressure load and blood pressure variability (Fig. 2). In cross-sectional study, we demonstrated that a
Metronomic breathing C O N T R O L
IV
E/I ratio IIb press
Present HRV
P A R K I N S O N
Valsalva manoeuvre
BP
in IIb, BP overshot in IV
E/I ratio =0
IV IIb press
Missing HRV
BP
in IIb, No BP overshot in IV
Fig. 1. Examples of physiological (CONTROL) and pathological (PARKINSON) autonomic testing during metronomic breathing and Valsalva manoeuvre. Systolic and diastolic blood pressures are defined by the blue lines, heart rate by red lines. During pathological metronomic breathing, no heart rate variability is present with an E/I ratio of 0. During pathological valsalva manoeuvre, no increase of blood pressure (BP) in phase IIb as well no overshot of BP in phase IV can be demonstrated.
T. Ziemssen, H. Reichmann / Journal of the Neurological Sciences 310 (2011) 129–132
Tilt table: Passive orthostasis C O N T R O L
24h ambulatory blood pressure
tilting
No BPsys drop P A R K I N S O N
131
BP
at night
BP
at night
tilting
BPsys drop
Fig. 2. Examples of physiological (CONTROL) and pathological (PARKINSON) autonomic testing during tilt testing and 24 h ambulatory blood pressure measurement (ABPM). Systolic and diastolic blood pressures are defined by the blue lines, heart rate by red lines. During pathological tilt testing, significant orthostatic hypotension is present which recovers slowly after tilting back. During pathological 24 h ABPM, a paradox and pathological increase of BP during night can be demonstrated as well as blood pressure peaks and falls during the day.
large proportion of PD and MSA patients exhibited an altered 24 h blood pressure profile including loss of the nocturnal blood pressure dip [26]. We also demonstrated significant correlations between orthostatic hypotension and altered ABPM. Intriguingly, orthostatic hypotension often coincides with paradoxical supine hypertension in
PD patients with advanced dysautonomia and in MSA patients which can be identified by 24 h ABPM or passive orthostasis [26]. Although a pathological 24 ABPM profile is not specific for patients with extrapyramidal disease, it provides a simple diagnostic modality if a specialized autonomic lab is not available.
Step I – Screening
Standardized questionnaire of autonomic function
plus
24 h ambulatory blood pressure measurement, Active standing (Schellong-Test)
Step II –Detailed examination in an autonomic center If step 1 screening demonstrates significant abnormalities, specialized autonomic testing: Tilt table testing (diagnosis of orthostatic hypotension, supine hypertension) MIBG scintigraphy (differential diagnosis: Parkinson´s diease vs. Multiple System Atrophy) Pupillography (differential diagnosis: Progressive supranuclear palsy) Detailed autonomic testing (eg. metronomic breathing, Valsalva manoeuvre, handgrip test) Test of non-cardiovascular functional system (eg. gastrointestinal, sweating) Innovative tests: Spectral analysis, baroreflex testing
Step III – Follow up Standardized questionnaire of autonomic function Tilt table testing (orthostatic hypotension) 24 h ambulatory blood pressure measurement
Fig. 3. Workup plan proposed by the autonomic lab in Dresden for autonomic testing in patients with extrapyramidal disorders.
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T. Ziemssen, H. Reichmann / Journal of the Neurological Sciences 310 (2011) 129–132
7. Spectral and baroreflex analysis Heart rate fluctuations, which reflect modulation of sinus node activity by autonomic and other homeostatic mechanisms, can be quantified by spectral analysis [27]. Thus, the spectral analysis of heart rate may identify autonomic inputs and their changes to the heart. Moreover, in a group of PD patients we found pathological heart rate spectra which were related to the disease stage of the patients [28,29]. The response of heart rate to a given change of systolic blood pressure mediated by the baroreflex arc is a fundamental characteristic of the short-term regulation of the cardiovascular system [30,31]: An increase of blood pressure will be counterregulated by a decrease of heart rate, and vice versa. To assess the function of the baroreflex arc, baroreflex gain or sensitivity (BRS) is calculated by measuring the changes of heart rate in response to blood pressure changes [32]. The impairment of baroreflex function plays an adverse role in a wide range of diseases as we have recently shown in extrapyramidal diseases [28,29]. 8. Conclusions Autonomic testing batteries provide multiple well-validated, sensitive, and non-invasive tests to diagnose, quantify, and characterize clinical autonomic disorders. Since tests are sensitive to external influences such as noise, room temperature, and humidity these should be performed under standardized conditions. Patients with extrapyramidal disorders unquestionably benefit from testing to guide symptomatic and disease specific therapy and to aid with diagnosis and management. At present, the pattern of abnormalities on formal testing is not specific enough to definitively separate different extrapyramidal syndromes, but the findings can reinforce or support the clinical diagnosis. Our laboratory in Dresden has established a workup plan for patients with extrapyramidal disease (Fig. 3). This workup plan has been based on clinical experience since scientific data are scarce or lacking. We suggest that screening for autonomic dysfunction should be performed in all patients with extrapyramidal disease. This screening should include a standardized autonomic questionnaire [33], an active standing test and 24 h ABPM [26]. In the case of pathological findings, detailed autonomic testing should follow including spectral and baroflex analysis as well as passive orthostasis for the quantification of orthostatic hypotension and of supine hypertension [34]. In addition, pupillography demonstrating miosis is most useful for the diagnosis of PSP [9]. MIBG scintigraphy can also be applied to differentiate preganglionic (eg. MSA) from postganglionic syndromes (eg. PD) [35]. Autonomic testing should be repeated during follow up visits. In the follow up, application of standardized questionnaires, tilt table testing and 24 h ABPM seems to be helpful to monitor cardiovascular dysautonomia and to adapt symptomatic treatment to the current cardiovascular autonomic status. Disclosures Nothing to disclose. References [1] Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson's disease. Parkinsonism Relat Disord Aug. 2007;13(6):323–32. [2] Witjas T, Kaphan E, Azulay JP, Blin O, Ceccaldi M, Pouget J, et al. Nonmotor fluctuations in Parkinson's disease: frequent and disabling. Neurology Aug. 13 2002;59(3):408–13. [3] Reichmann H, Ziemssen T. Treatment strategies for nonmotor manifestations of Parkinson's disease. Expert Opin Pharmacother Apr. 2009;10(5):773–84. [4] Walter BL. Cardiovascular autonomic dysfunction in patients with movement disorders. Cleve Clin J Med Mar. 2008;75(Suppl 2):S54–8. [5] Appenzeller O, Goss JE. Autonomic deficits in Parkinson's syndrome. Arch Neurol Jan. 1971;24(1):50–7.
[6] Reimann M, Schmidt C, Herting B, Prieur S, Junghanns S, Schweitzer K, et al. Comprehensive autonomic assessment does not differentiate between Parkinson's disease, multiple system atrophy and progressive supranuclear palsy. J Neural Transm Sep. 17 2010;117(1):69–76. [7] Wenning GK, Ben-Shlomo Y, Hughes A, Daniel SE, Lees A, Quinn NP. What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson's disease? J Neurol Neurosurg Psychiatry Apr. 2000;68(4):434–40. [8] Schmidt C, Herting B, Prieur S, Junghanns S, Schweitzer K, Globas C, et al. Autonomic dysfunction in different subtypes of multiple system atrophy. Mov Disord 2008 Sep 15;23(12):1766–72. [9] Schmidt C, Herting B, Prieur S, Junghanns S, Schweitzer K, Globas C, et al. Pupil diameter in darkness differentiates progressive supranuclear palsy (PSP) from other extrapyramidal syndromes. Mov Disord Oct. 31 2007;22(14):2123–6. [10] Goldstein DS. Dysautonomia in Parkinson's disease: neurocardiological abnormalities. Lancet Neurol Nov. 2003;2(11):669–76. [11] Oka H, Yoshioka M, Morita M, Onouchi K, Suzuki M, Ito Y, et al. Reduced cardiac 123I-MIBG uptake reflects cardiac sympathetic dysfunction in Lewy body disease. Neurology Oct. 2 2007;69(14):1460–5. [12] Rub U, Del Tredici K, Schultz C, de Vos RA, Jansen Steur EN, Arai K, et al. Progressive supranuclear palsy: neuronal and glial cytoskeletal pathology in the higher order processing autonomic nuclei of the lower brainstem. Neuropathol Appl Neurobiol Feb. 2002;28(1):12–22. [13] Postuma RB, Montplaisir J. Predicting Parkinson's disease — why, when, and how? Parkinsonism Relat Disord Dec. 2009;15(Suppl 3):S105–9. [14] Sakakibara R, Uchiyama T, Yamanishi T, Shirai K, Hattori T. Bladder and bowel dysfunction in Parkinson's disease. J Neural Transm 2008;115(3):443–60. [15] Jost WH. Autonomic dysfunctions in idiopathic Parkinson's disease. J Neurol Feb. 2003;250(Suppl 1):I28–30. [16] Schatz IJ. Orthostatic hypotension predicts mortality. Lessons from the Honolulu Heart Program. Clin Auton Res Aug. 2002;12(4):223–4. [17] Bennett DA, Beckett LA, Murray AM, Shannon KM, Goetz CG, Pilgrim DM, et al. Prevalence of parkinsonian signs and associated mortality in a community population of older people. N Engl J Med Jan. 11 1996;334(2):71–6. [18] Ben-Shlomo Y, Marmot MG. Survival and cause of death in a cohort of patients with parkinsonism: possible clues to aetiology? J Neurol Neurosurg Psychiatry Mar. 1995;58(3):293–9. [19] Ziemssen T, Reichmann H. Cardiovascular autonomic dysfunction in Parkinson's disease. J Neurol Sci Sep. 7 2010;289(1–2):74–80. [20] Schmidt C, Herting B, Prieur S, Junghanns S, Schweitzer K, Reichmann H, et al. Autonomic dysfunction in patients with progressive supranuclear palsy. Mov Disord Oct. 30 2008;23(14):2083–9. [21] Schmidt C, Herting B, Prieur S, Junghanns S, Schweitzer K, Globas C, et al. Valsalva manoeuvre in patients with extrapyramidal disease. J Neural Transm 2009;116 (7):875–80. [22] Kaufmann H. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Auton Res Apr. 1996;6 (2):125–6. [23] Robertson D. The pathophysiology and diagnosis of orthostatic hypotension. Clin Auton Res Mar. 2008;18(Suppl 1):2–7. [24] Peralta C, Stampfer-Kountchev M, Karner E, Kollensperger M, Geser F, Wolf E, et al. Orthostatic hypotension and attention in Parkinson's disease with and without dementia. J Neural Transm 2007;114(5):585–8. [25] Bleasdale-Barr KM, Mathias CJ. Neck and other muscle pains in autonomic failure: their association with orthostatic hypotension. J R Soc Med Jul. 1998;91(7):355–9. [26] Schmidt C, Berg D, Prieur S, Junghanns S, Schweitzer K, Globas C, et al. Loss of nocturnal blood pressure fall in various extrapyramidal syndromes. Mov Disord Oct. 30 2009;24(14):2136–42. [27] Reimann M, Friedrich C, Gasch J, Reichmann H, Rudiger H, Ziemssen T. Trigonometric regressive spectral analysis reliably maps dynamic changes in baroreflex sensitivity and autonomic tone: the effect of gender and age. PLoS One 2010;5(8):e12187. [28] Friedrich C, Rudiger H, Schmidt C, Herting B, Prieur S, Junghanns S, et al. Baroreflex sensitivity and power spectral analysis during autonomic testing in different extrapyramidal syndromes. Mov Disord Dec. 11 2010;25(3):315–24. [29] Friedrich C, Rudiger H, Schmidt C, Herting B, Prieur S, Junghanns S, et al. Baroreflex sensitivity and power spectral analysis in different extrapyramidal syndromes. J Neural Transm Nov. 2008;115(11):1527–36. [30] Karemaker JM, Wesseling KH. Variability in cardiovascular control: the baroreflex reconsidered. Cardiovasc Eng (Dordrecht, Netherlands) Mar. 2008;8(1):23–9. [31] Mense L, Reimann M, Rudiger H, Gahn G, Reichmann H, Hentschel H, et al. Autonomic function and cerebral autoregulation in patients undergoing carotid endarterectomy. Circ J Oct. 2010;74(10):2139–45. [32] Parati G, Di Rienzo M, Mancia G. How to measure baroreflex sensitivity: from the cardiovascular laboratory to daily life. J Hypertens Jan. 2000;18(1):7–19. [33] Visser M, Marinus J, Stiggelbout AM, Van Hilten JJ. Assessment of autonomic dysfunction in Parkinson's disease: the SCOPA-AUT. Mov Disord Nov. 2004;19 (11):1306–12. [34] Ziemssen T, Fuchs G, Greulich W, Reichmann H, Schwarz M, Herting B. Treatment of dysautonomia in extrapyramidal disorders. J Neurol 2011;258(Suppl 2): S339–45. [35] Courbon F, Brefel-Courbon C, Thalamas C, Alibelli MJ, Berry I, Montastruc JL, et al. Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson's disease. Mov Disord Aug. 2003;18(8):890–7.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Cardiovascular autonomic testing in extrapyramidal disorders Tjalf Ziemssen a, b,⁎, Heinz Reichmann b a b
ANF-lab, Neurological University Clinic, Dresden, Germany Neurological University Clinic, Dresden, Germany
a r t i c l e
i n f o
Article history: Received 9 March 2011 Received and in revised form 28 June 2011 Accepted 19 July 2011 Available online 11 August 2011 Keywords: Parkinson's disease Cardiovascular dysautonomia Orthostatic hypotension Autonomic testing
a b s t r a c t Various diagnostic tests are available to demonstrate autonomic failure in extrapyramidal disease. Autonomic function tests can identify parasympathetic and sympathetic dysfunction. While specialized tests are only available in autonomic labs, routine tests such as 24 h ambulatory blood pressure measurements can be broadly used in clinical practice eg. as screening tests. In this review, we briefly introduce functional cardiovascular autonomic testing and propose a workup plan for patients with extrapyramidal disease. In all patients with extrapyramidal disease, screening for autonomic dysfunction should be performed. In the case of pathological findings, detailed autonomic testing should be considered with repeated measurements at follow up visits. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Recognition of autonomic dysfunction continues to improve, in part aided by advances in non-invasive clinical testing. Especially in extrapyramidal disorders, autonomic symptoms are common but underrated and neglected in terms of treatment [1–3]. The prevalence of dysautonomia in PD varies between 14 and 80% depending on the collective and methodology [4], a subjective impairment of daily life is reported by more than half of PD patients [5]. Especially patients with atypical Parkinsonian syndromes like multiple system atrophy (MSA) usually present early in the disease process with fast progressing dysautonomia. The differentiation between PD with advanced dysautonomia and MSA is challenging and requires the use of sophisticated diagnostic techniques [6,7]. There are no significant differences of autonomic dysfunction between the different MSA subtypes [8]. Even patients with progressive supranuclear palsy (PSP) have been shown to develop autonomic dysfunction to a certain degree [9]. Dysfunction of postganglionic sympathetic efferences is widely regarded as primary cause of dysautonomia in PD while postganglionic lesions are not present in MSA. Unlike PD patients, MSA patients feature pronounced central autonomic abnormalities as do PSP patients [10,12]. In dementia with Levy bodies (DLB), autonomic
dysfunction may result from preganglionic dysfunction in addition to postganglionic dysfunction [11]. Thus, the evaluation of the autonomic function is crucial for diagnosis and treatment at different stages of disease [13]. Dysautonomia commonly occurs more frequently in advanced stages of the disease. It impacts on the subjective picture of the symptoms, the quality of life and renders individual treatment schemes necessary [14,15]. Cardiovascular dysautonomia particularly characterized by orthostatic hypotension has been shown to be a significant independent predictor of mortality [16]. Studies from cardiology and diabetology have shown that the impairment of autonomic reflexes plays an important adverse role. Increased cardiovascular mortality has been reported in patients with different extrapyramidal disorders. The mortality of PD patients is almost doubled compared with that of age and sex-matched healthy controls [17]. In a 20-year follow-up study, Ben-Shlomo and Marmot demonstrated an increase in heart ischemia related deaths which may account for the increased mortality in extrapyramidal disorders [18]. Cardiovascular autonomic dysfunction could be at least partly responsible for the increased cardiac mortality in patients with extrapyramidal disease [19]. Therefore, cardiovascular autonomic testing may be of prognostic/predictive value for cardiovascular mortality in patients with extrapyramidal diseases. 2. Autonomic cardiovascular testing
⁎ Corresponding author at: Autonomes und neuroendokrinologisches Funktionslabor, Klinik und Poliklinik für Neurologie, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, D-01307 Dresden, Germany. Tel.: +49 351 458 3859; fax: +49 351 458 5873. E-mail address: [email protected] (T. Ziemssen). URL: http://www.neuro.med.tu-dresden.de (T. Ziemssen). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.07.032
Unlike other systems, the function of the autonomic nervous system normally cannot be directly assessed. Instead, responses of complex overlapping autonomic reflex loops, most commonly of heart rate and blood pressure, are measured after controlled perturbations of the system. The techniques most widely used in the clinical setting
130
T. Ziemssen, H. Reichmann / Journal of the Neurological Sciences 310 (2011) 129–132
entail the measurement of an end-organ response to a physiological provocation [19]. In this review, these tests of cardiovascular autonomic function will be presented: 3. Heart rate variability (HRV) Heart rate variability during deep metronomic breathing (6 cycles/min) is the most widely used index of cardiovagal parasympathetic function including the expiratory to inspiratory ratio (E:I ratio) (Fig. 1). Other tests that measure parasympathetic cardiovagal functioning include measures of HRV during rest, coughing, diving reflex, standing, squatting, and active lying down. The heart rate (HR) response to the Vasalva manoeuvre is discussed below. While parameters like E:I ratio are considered to be measures in the time domain, HR analysis in the frequency domain is increasingly applied. The power in specific frequency bands correlates to higher frequency respiratory (parasympathetic) or slower midrange primarily adrenergic activity. A ratio of high to low band power produces a “balance” measure of parasympathetic and sympathetic tone. This activity can be monitored at rest and under different cardiovascular conditions. Our group could demonstrate highly prevalent cardiovagal failure in patients with PD, MSA and PSP [8,20]. 4. Valsalva manoeuvre (VM) The Valsalva manoeuvre (VM) is a reliable and reproducible method that provides information regarding parasympathetic and sympathetic function. VM is typically performed by blowing through a mouthpiece connected to a mercury manometer (40 mmHg) for 15 s (Fig. 1). A direct measure of the hemodynamic response to the VM can be obtained with a non-invasive beat-to-beat blood pressure monitor. The decrease in blood pressure during the early phase II, the recovery
of blood pressure in late phase II and the increase in blood pressure during phase IV of the VM serve as measures of vasomotor adrenergic function [21]. The Valsalva ratio (VR) is a measure of cardiovagal functioning which is calculated by dividing the R–R interval of the HR nadir over the HR peak during this period. Normative values of VR are well established and decline with age. VM abnormalities are also highly prevalent in patients with PD, MSA and PSP [8,20,21]. 5. Active or passive orthostasis The most frequently performed cardiovascular test of the sympathetic nervous system function is the blood pressure response to postural change (active standing or passive tilting). Passive tilting on a tilt-table provokes more exaggerated blood pressure responses than active standing since it minimizes the compensatory response resulting from active muscle contraction. Hence, it has been suggested to be more sensitive (Fig. 2). Orthostatic hypotension, the most frequent symptom of cardiovascular autonomic dysfunction [23,24], occurs when the systolic blood pressure decreases at least 20 mm Hg or the diastolic blood pressure at least 10 mm Hg within 3 min of 60° upright tilt or of standing [22]. Orthostatic hypotension can be asymptomatic or symptomatic. Symptoms generally encompass dizziness, weakness, nausea, pain or blurred vision. Roughly 50% of PD patients with advanced disease stages complain about general symptoms of orthostatic hypotension upon standing [25]. 6. 24 h ambulatory blood pressure measurement (ABPM) 24 h ambulatory blood pressure monitoring (ABPM) allows for determination of the circadian blood pressure load and blood pressure variability (Fig. 2). In cross-sectional study, we demonstrated that a
Metronomic breathing C O N T R O L
IV
E/I ratio IIb press
Present HRV
P A R K I N S O N
Valsalva manoeuvre
BP
in IIb, BP overshot in IV
E/I ratio =0
IV IIb press
Missing HRV
BP
in IIb, No BP overshot in IV
Fig. 1. Examples of physiological (CONTROL) and pathological (PARKINSON) autonomic testing during metronomic breathing and Valsalva manoeuvre. Systolic and diastolic blood pressures are defined by the blue lines, heart rate by red lines. During pathological metronomic breathing, no heart rate variability is present with an E/I ratio of 0. During pathological valsalva manoeuvre, no increase of blood pressure (BP) in phase IIb as well no overshot of BP in phase IV can be demonstrated.
T. Ziemssen, H. Reichmann / Journal of the Neurological Sciences 310 (2011) 129–132
Tilt table: Passive orthostasis C O N T R O L
24h ambulatory blood pressure
tilting
No BPsys drop P A R K I N S O N
131
BP
at night
BP
at night
tilting
BPsys drop
Fig. 2. Examples of physiological (CONTROL) and pathological (PARKINSON) autonomic testing during tilt testing and 24 h ambulatory blood pressure measurement (ABPM). Systolic and diastolic blood pressures are defined by the blue lines, heart rate by red lines. During pathological tilt testing, significant orthostatic hypotension is present which recovers slowly after tilting back. During pathological 24 h ABPM, a paradox and pathological increase of BP during night can be demonstrated as well as blood pressure peaks and falls during the day.
large proportion of PD and MSA patients exhibited an altered 24 h blood pressure profile including loss of the nocturnal blood pressure dip [26]. We also demonstrated significant correlations between orthostatic hypotension and altered ABPM. Intriguingly, orthostatic hypotension often coincides with paradoxical supine hypertension in
PD patients with advanced dysautonomia and in MSA patients which can be identified by 24 h ABPM or passive orthostasis [26]. Although a pathological 24 ABPM profile is not specific for patients with extrapyramidal disease, it provides a simple diagnostic modality if a specialized autonomic lab is not available.
Step I – Screening
Standardized questionnaire of autonomic function
plus
24 h ambulatory blood pressure measurement, Active standing (Schellong-Test)
Step II –Detailed examination in an autonomic center If step 1 screening demonstrates significant abnormalities, specialized autonomic testing: Tilt table testing (diagnosis of orthostatic hypotension, supine hypertension) MIBG scintigraphy (differential diagnosis: Parkinson´s diease vs. Multiple System Atrophy) Pupillography (differential diagnosis: Progressive supranuclear palsy) Detailed autonomic testing (eg. metronomic breathing, Valsalva manoeuvre, handgrip test) Test of non-cardiovascular functional system (eg. gastrointestinal, sweating) Innovative tests: Spectral analysis, baroreflex testing
Step III – Follow up Standardized questionnaire of autonomic function Tilt table testing (orthostatic hypotension) 24 h ambulatory blood pressure measurement
Fig. 3. Workup plan proposed by the autonomic lab in Dresden for autonomic testing in patients with extrapyramidal disorders.
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T. Ziemssen, H. Reichmann / Journal of the Neurological Sciences 310 (2011) 129–132
7. Spectral and baroreflex analysis Heart rate fluctuations, which reflect modulation of sinus node activity by autonomic and other homeostatic mechanisms, can be quantified by spectral analysis [27]. Thus, the spectral analysis of heart rate may identify autonomic inputs and their changes to the heart. Moreover, in a group of PD patients we found pathological heart rate spectra which were related to the disease stage of the patients [28,29]. The response of heart rate to a given change of systolic blood pressure mediated by the baroreflex arc is a fundamental characteristic of the short-term regulation of the cardiovascular system [30,31]: An increase of blood pressure will be counterregulated by a decrease of heart rate, and vice versa. To assess the function of the baroreflex arc, baroreflex gain or sensitivity (BRS) is calculated by measuring the changes of heart rate in response to blood pressure changes [32]. The impairment of baroreflex function plays an adverse role in a wide range of diseases as we have recently shown in extrapyramidal diseases [28,29]. 8. Conclusions Autonomic testing batteries provide multiple well-validated, sensitive, and non-invasive tests to diagnose, quantify, and characterize clinical autonomic disorders. Since tests are sensitive to external influences such as noise, room temperature, and humidity these should be performed under standardized conditions. Patients with extrapyramidal disorders unquestionably benefit from testing to guide symptomatic and disease specific therapy and to aid with diagnosis and management. At present, the pattern of abnormalities on formal testing is not specific enough to definitively separate different extrapyramidal syndromes, but the findings can reinforce or support the clinical diagnosis. Our laboratory in Dresden has established a workup plan for patients with extrapyramidal disease (Fig. 3). This workup plan has been based on clinical experience since scientific data are scarce or lacking. We suggest that screening for autonomic dysfunction should be performed in all patients with extrapyramidal disease. This screening should include a standardized autonomic questionnaire [33], an active standing test and 24 h ABPM [26]. In the case of pathological findings, detailed autonomic testing should follow including spectral and baroflex analysis as well as passive orthostasis for the quantification of orthostatic hypotension and of supine hypertension [34]. In addition, pupillography demonstrating miosis is most useful for the diagnosis of PSP [9]. MIBG scintigraphy can also be applied to differentiate preganglionic (eg. MSA) from postganglionic syndromes (eg. PD) [35]. Autonomic testing should be repeated during follow up visits. In the follow up, application of standardized questionnaires, tilt table testing and 24 h ABPM seems to be helpful to monitor cardiovascular dysautonomia and to adapt symptomatic treatment to the current cardiovascular autonomic status. Disclosures Nothing to disclose. References [1] Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson's disease. Parkinsonism Relat Disord Aug. 2007;13(6):323–32. [2] Witjas T, Kaphan E, Azulay JP, Blin O, Ceccaldi M, Pouget J, et al. Nonmotor fluctuations in Parkinson's disease: frequent and disabling. Neurology Aug. 13 2002;59(3):408–13. [3] Reichmann H, Ziemssen T. Treatment strategies for nonmotor manifestations of Parkinson's disease. Expert Opin Pharmacother Apr. 2009;10(5):773–84. [4] Walter BL. Cardiovascular autonomic dysfunction in patients with movement disorders. Cleve Clin J Med Mar. 2008;75(Suppl 2):S54–8. [5] Appenzeller O, Goss JE. Autonomic deficits in Parkinson's syndrome. Arch Neurol Jan. 1971;24(1):50–7.
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