Clinical Neurophysiology 125 (2014) 1248–1254
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Spectrum of autonomic dysfunction in orthostatic dizziness Hyun-Ah Kim, Hyon-Ah Yi, Hyung Lee ⇑ Department of Neurology, Keimyung University School of Medicine, Daegu, Republic of Korea Brain Research Institute, Keimyung University School of Medicine, Daegu, Republic of Korea
a r t i c l e
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Article history: Accepted 19 October 2013 Available online 5 November 2013 Keywords: Orthostatic dizziness Autonomic dysfunction Spectrum
h i g h l i g h t s This study investigated the frequency and detailed spectrum of autonomic dysfunction in patients
with orthostatic dizziness. Approximately 83% (180/217) of patients showed at least one abnormal autonomic testing result. We
classified orthostatic dizziness into 11 groups according to the patterns of autonomic dysfunctions. This study helps clinicians to understand the pattern and mechanism of autonomic dysfunction asso-
ciated with orthostatic dizziness.
a b s t r a c t Objective: To investigate the frequency and detailed spectrum of autonomic dysfunction in patients with orthostatic dizziness (OD). Methods: Over 20 months, 217 consecutive patients with OD as a presenting symptom of orthostatic intolerance were enrolled. The distribution and severity of autonomic dysfunction were measured by the composite autonomic severity score (CASS), which was derived from a standard autonomic function test including Finapres for recording of the beat-to-beat blood pressure. Sympathetic indexes (SIs) were calculated from the Valsalva maneuver (VM). Results: Approximately 83% of patients showed at least one abnormal autonomic testing result. We classified OD into 11 groups according to the patterns of autonomic dysfunctions. The most common pattern was generalized autonomic failure of sympathetic adrenergic and parasympathetic cardiovagal functions (n = 60). Patients with delayed OH had larger BP increases during late phase II of the VM (p = 0.04), showed greater phase IV overshoot (p = 0.04), and had a smaller pressure recovery time increase (p = 0.02) than patients with classic OH. Each SI showed the strongest correlation with the CASS adrenergic subscores. Conclusions: OD can present with a board spectrum of autonomic dysfunctions. Significance: This investigation could be useful in understanding the pattern and mechanism of autonomic dysfunction associated with OD. Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Orthostatic dizziness (OD) is a common dizzy syndrome characterized by non-vertiginous light-headedness when a patient rises to standing from a sitting or supine position (Baloh and Kerber, 2011). OD is a common complaint in not only general practice and but specialized dizziness clinics. OD is believed to be one of ⇑ Corresponding author at: Department of Neurology, Keimyung University School of Medicine, 194 Dongsan dong, Daegu 700-712, Republic of Korea. Tel.: +82 53 250 7835; fax: +82 53 250 7840. E-mail address: [email protected] (H. Lee).
the most common causes of non-vestibular dizziness (Baloh and Kerber, 2011; Radtke et al., 2011). A recent report showed that the one year and lifetime prevalence of OD were 10.9% and 12.5%, respectively (Radtke et al., 2011). Although OD usually results from orthostatic hypotension (OH) and is considered a representative sign of sympathetic autonomic dysfunction (Kim et al., 2013), the types of OH that may occur in patients with OD has not been described. Moreover, the frequency and pattern of other accompanying autonomic dysfunctions are not known. To study these problems, we prospectively investigated the autonomic test results of all the patients referred to our autonomic laboratory for evaluation of OD during a 20-month period.
1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.10.022
H.-A. Kim et al. / Clinical Neurophysiology 125 (2014) 1248–1254
2. Methods From July 2011 to February 2013, 300 patients with OD as a presenting symptom of orthostatic intolerance were initially included in this study. Most were referred to our autonomic laboratory for evaluation of OD. We defined OD as follows: (1) patients had non-vestibular dizziness including diffuse non-rotational dizziness, light-headedness, fogginess in the head, or a feeling of an impending black out and (2) dizziness that occurs only by postural changes, such as standing up from a sitting or supine position. After excluding 83 patients with OD, 217 patients were finally enrolled for this study. Among 83 excluded patients, 57 showed a flat top response during the Valsalva maneuver (VM) that was defined as an increase in the blood pressure (BP) response by at least 20 mmHg above baseline for at least 10 s, and 15 had significant arrhythmia with atrial fibrillation. Other had inadequate evaluations. A standardized battery of autonomic tests, including the headup tilt test, VM, Valsalva ratio (VR), heart rate response to deep breathing using Finometer devices (FMS, Amsterdam, The Netherlands) for recording beat-to-beat BP and heart rate (HR) response and the quantitative sudomotor axon reflex test, was performed in all the patients according to a previously validated method for the diagnosis of autonomic dysfunction (Low and Benarroch, 2008). For VM, patients were instructed to take a deep breath and blow into a syringe through a mouthpiece attached to a manometer for 15 s until expiratory pressure was reached to 40 mmHg. BP magnitude was determined for four phases, i.e., phase I, early and late phase II, phase III, and phase IV as previously described (Low, 1993; Low and Benarroch, 2008). A maximal drop in the mean blood pressure (MBP) of more than 20 mmHg during early phase II was abnormal (Novak, 2011b). Late phase II was considered abnormal if the magnitude of the end of phase II did not exceed the baseline (i.e., a negative value) (Novak, 2011b). Phase IV was considered abnormal if the magnitude of the phase IV response failed to reach the baseline (i.e., a negative value) (Novak, 2011a,b). The sympathetic indexes (SIs), including the reduction of early phase II (SI 1), magnitude of late phase II (SI 2), difference in BP between the baseline and the end of phase 2 (SI 3), magnitude of phase IV (SI 4), pressure recovery time (PRT, SI 5), and adrenergic baroreflex sensitivity index (SI 6) that have been linked to sympathetic adrenergic failure (SAF), were calculated and determined as abnormality from VM results (Novak, 2011a). The HR response was defined as the average HR difference (maximum– minimum) of the five largest consecutive responses (i.e., HRDB), and expiration/inspiration (E/I) ratio during deep breathing was calculated. The VR was derived from the maximum HR divided by the lowest HR following VM. The tilt protocol included at least 10 min in the supine position and 20 min of a tilt at 70 degrees. OH was defined by a decrease in systolic blood pressure (SBP) of at least 20 mmHg or a decrease in diastolic blood pressure (DBP) of at least 10 mmHg between supine rest for 10 min and an upright posture for 20 min (The Consensus Committee of the American Autonomic Society and the American Academy of Neurology, 1996). Classic OH was defined as a decrease in systolic BP P 20 mmHg or in diastolic BP P 10 mmHg within 3 min of tilting. Delayed OH was defined as a slow progressive decrease in SBP that occurred after 3 min of tilting. Early OH was characterized by a decrease in SBP of 40 mmHg or more, immediately (within 30 s) after tilting, with rapid normalization of the BP response after 30 s. Transient OH was defined as an orthostatic reduction in SBP of at least 20 mmHg or a decrease in DBP of at least 10 mmHg any time during the tilting except for the initial 30 s, but decreased BP response was normalised within a few minutes after the onset of orthostatic reduction. The postural orthostatic tachycardia
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syndrome (POTS) was characterized by a sustained HR increment of 30 beats per minute within 10 min of the head-up tilt in the absence of OH (Thieben et al., 2007). Postganglionic sympathetic sudomotor functions were analyzed by quantitative sudomotor axonal reflex test (QSART) at the forearm, proximal leg, and distal leg using Q-Sweat machine (WR Medical Electronics, Stillwater, MN). The volume of capsules was 0.1229 cm2, stimulation current was 2 mA, and duration of stimulation was 5 min. The sweat volume was collected for 10 min. The pattern and severity of autonomic dysfunctions in patients with OD were determined based on the composite autonomic severity score (CASS) that consisted of each subscore evaluating the sympathetic adrenergic and cholinergic, and parasympathetic cardiovagal autonomic functions (Low, 1993; Low et al., 1995, 2013). In our study, isolated POTS was not included as a possible pattern of autonomic dysfunction because it was not recognized as an abnormality in the CASS calculation. All patients were asked to complete the Korean version of the orthostatic grading scale (KOGS), which is known to be a reliable and valid tool for screening patients with OD in Korea(Kim et al., 2013). We did not exclude patients who were receiving medications with potential effects on autonomic function, such as beta-blockers, anticholinergic agents, and antihypertensive drugs because medication is also a common cause of OD. No coffee, food, or nicotine was permitted for 6 h before the study. Because this study included all consecutive patients with OD during research period, 32 patients previously reported (Kim et al., 2013) were included for completeness of the data. However, new information is added in this report. All experiments complied with the tenets of the Declaration of the Helsinki and the study was approved by the Institutional Review Board. We compared the clinical characteristics and autonomic test result data between patients with classic OH and patients with delayed OH using the independent-samples t-test for continuous variables and chi-squared test for categorical variables. The mean value ± standard deviation (SD) is displayed. A probability of p < 0.05 was considered to be statistically significant.
3. Results Our study consisted of 217 patients with a mean age of 57.1 years (SD, 16.1 years) and an even distribution of men (52%) and women. In addition to orthostatic intolerance (100%) as a presenting symptom for inclusion to this study, patients commonly complained of blurred vision (74%) weakness or tiredness (70%), and difficulty in concentration or thinking mimicking cognitive impairments (47%). The symptoms of sympathetic hyperexcitation, including tremor and chest palpitation, were noted in approximately 40% of patients. A history of syncope was noted in approximately 15% of patients. The patients’ pre-test diagnoses included 47% with hypertension, 29% with diabetes, 12% with ischemic heart disease, 11% with Parkinson’s disease, 9.7% with benign prostatic hypertrophy, 5.1% with multiple system atrophy, and 4.1% with other medical illness, including thyroid disease or systemic cancer. Thirty-seven percent (81/217) of patients had no medical illness. A total of 180 patients (83%) had at least one abnormal autonomic testing result based on an abnormality of each test in the CASS. Most (147/180, 82%) patients had abnormalities related to sympathetic adrenergic failure. If the patients with isolated POTS (n = 7) were included, 86% (187/217) of patients showed at least one abnormal autonomic result. We classified OD into 11 groups according to the patterns of autonomic impairment (Table 1).
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Table 1 Frequenciesa of autonomic dysfunctions in 217 patients with orthostatic dizziness. Frequency (n = 217) Generalized autonomic failure with sympathetic adrenergic and parasympathetic cardiovagal dysfunctions Pan-autonomic failureb Sympathetic adrenergic failure with abnormal VM only Sympathetic adrenergic failure with OH and abnormal VM only Sympathetic adrenergic failure with OH only Generalized autonomic failure with sympathetic adrenergic and cholinergic dysfunctions Parasympathetic cardiovagal failure with abnormal HRDB only Sympathetic cholinergic failure with abnormal QSART only Generalized autonomic failure with parasympathetic cardiovagal and sympathetic cholinergic dysfunctions Parasympathetic cardiovagal failure with abnormal VR and HRDB Parasympathetic cardiovagal failure with abnormal VR only
27.7% (60/217) 16.6% (36/217) 7.4% (16/217) 6.5% (14/217) 5.1% (11/217) 4.6% (10/217) 4.6% (10/217) 3.7% (8/217) 3.2% (7/217) 2.8% (6/217) 0.9% (2/217)
a
Based on composite autonomic severity score. Means both sympathetic adrenergic and cholinergic, and parasympathetic cardiovagal dysfunctions. OH = orthostatic hypotension; VM = Valsalva maneuver; HRDB = heart rate response in deep breathing; VR = Valsalva ratio. b
The three most common patterns of the autonomic dysfunction were the generalized autonomic failure (n = 60) of sympathetic adrenergic and parasympathetic cardiovagal functions followed by pan-autonomic failure (n = 36), which was defined as a complete loss of sympathetic adrenergic and cholinergic as well as parasympathetic cardiovagal functions, and isolated SAF with only an abnormal VM result (n = 16). A total of 110 patients (51%) had OH on the tilt test. We identified four patterns of OH during tilting (Table 2) as follows: 53 patients (53/110, 48%) had OH during the first 3 min of testing that remained stable or continued, progressive decline until tilt back (classic OH), 24 patients (24/110, 24%) had OH beyond 3 min after tilting that remained stable or continued, progressive decline until tilt back (delayed OH), 21 patient (21/110, 19%) had OH beyond 30 s after tilting, but decreased response normalized within a few minutes after the onset of orthostatic reduction (transient OH), and 12 patients (12/110, 11%) had an initial drop of SBP of P40 mmHg within 30 s after tilting, but OH rapidly normalized (early OH). None of patients were taking medication to control their orthostatic symptoms. Illustrative cases with different patterns OF OH during the tilting are shown in Fig. 1A–D. Patients (n = 24) with classic OH had more severe falls in SBP, DBP, and MBP during tilting than those with delayed OH. The abnormalities of SI 2–6 were more severe in patients with classic OH than in patients with delayed OH, but falls in BP during early phase II of the VM (SI 1) were not different in both groups. The total scores of KOGS and CASS, CASS adrenergic subscore, and CASS cardiovagal subscore were significantly higher in patients with classic OH than in patients with delayed OH. Other factors were not different in both groups (Table 3). There was no difference in the autonomic function test results between early and transient OH except for two parameters. The total and cardiovagal scores of KOGS were somewhat higher in
Table 2 Results of tilt table testing. Frequency (n = 217) Normal OH Classic OH Delayed OH Transient OH Early OH Neurocardiogenic syncope POTS Dizzy sensation during tilt
40.5% (88/217) 50.7% (110/217) 24.4% (53/217) 11.1% (24/217) 9.7% (21/217) 5.5% (12/217) 2.8% (6/217) 8.7% (19/217) 32.7% (71/217)
OH; orthostatic hypotension, POTS; postural tachycardia syndrome.
patients with early OH than in patients with transient OH (Supplementary Table S1). Approximately 70% (147/217) of patients had SAF that appeared as OH or abnormal VM results. Seventy-four percent (161/217) of patients showed sympathetic adrenergic dysfunction including OH, abnormal VM results, or POTS, which might be responsible for OD. Forty-nine percent (128/217) of patients showed an abnormal BP response during VM. Forty-percent (86/217) of patients showed combined abnormalities in the tilt test and VM. Only 30% (65/217) of patients had normal results on both tilt and VM. Approximately 40% (42/107) of patients with no OH during tilting showed an abnormal BP response during VM, whereas 27% (24/89) patients with normal BP response during VM showed OH during tilting. Illustrative cases with different patterns of SAF during VM, according to the total KOGS scores are shown in Fig. 2A–D. Each SI correlated with the total and each item scores of CASS. The strongest correlation was with the CASS adrenergic subscores, followed by the cardiovagal subscores, and then the sudomotor subscores. Among the six SIs, SI 2 showed the strongest correlation with the CASS adrenergic subscores. The degree of correlation between each SI and CASS adrenergic subscores decreased in the following order of SI 2 > SI 5 > SI 4 > SI 3 > SI 6 > SI 1 (Table 4). The frequencies of abnormal SIs from VM decreased in the following order of SI 2 (54%) > SI 3 (49.3%) > SI 5 (40.6%) > SI 4 (25.3%) > SI 1 (9.7%). The overall correlation analysis between the total and each item scores of KOGS and the SI 1–6 showed a partial correlation. Among the six SIs, SI 3 showed the strongest correlation with the total and each item scores of KOGS. The degree of correlation with total KOGS scores decreased in the following order of SI 3 > SI 4 > SI 5 (Fig. 3). Other SIs were not correlated to total KOGS scores. 4. Discussion To the best of our knowledge, this is the by far largest series of OD focused on the detailed spectrum of autonomic dysfunction. In our series, approximately 83% (180/217) of patients with OD showed at least one abnormal autonomic function test result. The most common pattern of autonomic dysfunction in our series was sympathetic adrenergic failure, which was diagnosed by the presence of OH or abnormal BP responses from VM that were observed in approximately 70% (147/217) of patients. Our result suggests that an abnormal VM result is also common form of autonomic dysfunction in OD. In our series, 51% (110/213) of patients with OD showed OH, which is similar to the previously reported frequency (47%) of OH (Gibbons and Freeman, 2006). In contrast to the previously reported result (Gibbons and Freeman, 2006) that two OH patterns,
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Fig. 1. Beat-to-beat blood pressure in mmHg and heart rate response in beats per minutes over 35 min (10 min supine, 20 min tilting, and 5 min re-supine) in representative subjects with classic OH (A), delayed OH (B), early OH (C), and transient OH (D). OH, orthostatic hypotension.
e.g., classic and delayed OH, are found in patients with light-headedness or dizziness as the presenting symptom, we found four patterns of OH related to OD: classic, delayed, initial, and transient OH. It has recently been recognized that delayed OH is a common pattern of OH in addition to as classic OH observed in patients who present light-headedness or presyncopal dizziness (Gibbons and Freeman, 2006). However, a previous report (Gibbons and Freeman, 2006) used BP monitoring with a measurement of 1 min interval for diagnosis of OH that cannot detect brief episodes of transient or early OH, which constituted 30% of total OH in our study. Using continuous BP monitoring to detect beat-to-beat BP response, our analysis reveals that certain patients have OH not categorized as classic or delayed OH and documented two additional patterns of OH related to OD. Greater sensitivity of screening procedure using beat-to-beat BP recording would enable the detection of these brief OH. Similar to a previous study(Gibbons and Freeman, 2006), we found that patients with classic OH had more severe falls in BP during tilting and a reduced phase IV overshoot from VM than patients with delayed OH. However, a previous report (Gibbons and Freeman, 2006) did not compare the detailed measurements of sympathetic function using SIs between patients with classic OH
and patients with delayed OH. Our results demonstrated that in addition to phase IV abnormality (SI 4), many factors that indicate sympathetic function, such as SI 2, 3, 5, 6, and CASS adrenergic subscores, were also more severely impaired in patients with classic OH than in patients with delayed OH. Unlike the previous report (Gibbons and Freeman, 2006), BP decreases during early phase II of the VM (SI 1) did not differ between the groups. Because the initial BP decrease during early phase II of the VM may depend on conditions other than sympathetic activity, such as volume status–venous capacitance (Novak, 2011a), SI 1 may less accurately reflect the functional status of sympathetic adrenergic system. The current data on the frequencies of abnormal SIs from VM, in which an abnormal SI 1 was the least among SIs, also support the contribution of non-sympathetic activity in appearance of early phase II during VM. Our study confirmed the previous notion that delayed OH is associated with milder form of sympathetic adrenergic failure. Indeed, delayed OH may be considered a mild or early stage of sympathetic adrenergic failure. Early OH observed in some patients resembles an initial OH, a frequent but underestimated cause of orthostatic intolerance (Wieling et al., 2007; Thomas et al., 2009) Similar to an initial OH, this early OH is also accompanied by a remarkable decrement of
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Table 3 Demographics and autonomic findings in patients with classic and delayed OH.
Age (y) Men (%) Baseline SBP (mmHg) Mean SBP fall during tilt Mean DBP fall during tilt Mean MBP fall during tilt HRDB E/I ratio Valsalva ratio Early phase II fall during VM (SI 1) Late phase II increase during VM (SI 2) SI 3 Phase IV overshooting during VM (SI 4) PRT (SI 5) BRSa (SI 6) KOGS total score CASS total score Adrenergic subscore Cardiovagal subscore Sudomotor subscore
Classic OH (BP fall 3 min on tilt test, n = 24)
p-Value*
62.8 ± 14.0 51% 129.5 ± 21.3 32.8 ± 19.6 11.6 ± 11.6 19.7 ± 14.0 6.1 ± 5.2 1.1 ± 0.1 1.3 ± 0.3 13.8 ± 8.9 3.5 ± 6.2 11.5 ± 12.6 4.8 ± 11.8 14.0 ± 11.5 9.8 ± 9.9 9.5 ± 4.9 4.9 ± 2.6 2.7 ± 1.3 1.7 ± 1.2 0.6 ± 1.0
60.9 ± 15.3 52% 130.2 ± 18.5 18.4 ± 8.0 5.9 ± 5.7 10.2 ± 7.8 7.5 ± 4.4 1.1 ± 0.1 1.4 ± 0.3 12.8 ± 9.0 10.1 ± 9.6 2.3 ± 14.6 11.2 ± 13.9 6.4 ± 8.8 14.6 ± 9.7 6.9 ± 3.8 3.1 ± 2.1 1.8 ± 1.3 1.4 ± 1.0 0.3 ± 0.6
.607 .99 .891 .000 .005 .000 .234 .279 .248 .664 .004 .006 .040 .002 .050 .021 .003 .006 .018 .079
OH = orthostatic hypotension; VM = Valsalva maneuver; HRDB = heart rate response in deep breathing; E/I = expiration/inspiration; PRT = pressure recovery time; KOGS = Korean version of orthostatic grading scale; CASS = composite autonomic severity score; SBP = systolic blood pressure; DBP = diastolic blood pressure; MBP = mean blood pressure; SI = sympathetic index; SI1 = the reduction of early phase II; SI2 = the magnitude of late phase II; SI3 = the difference in mean BP between baseline and the end of phase II; SI4 = the magnitude of phase IV; SI5 = pressure recovery time; SI6 = adrenergic baroreflex sensitivity (BRSa). * Chi-squared test for categorical variables and t-test for continuous variables.
SBP during the initial period of tilting, followed by a rapid and spontaneous normalization of BP. Thus, the period of hypotension is short. Unlike an initial OH that is exclusively associated with active standing up (Wieling et al., 2007; Thomas et al., 2009), early OH may occur in a condition of passive tilting, as observed in our patients. Initial OH commonly accompanies light-headedness, dizziness, and nausea as symptoms of orthostatic intolerance, whereas early OH documented during passive tilting is usually asymptomatic. Only monitoring of the beat-to-beat BP is critical for the objective documentation of both types of OH (Wieling et al., 2007; Thomas et al., 2009). Considering that nearly entire autonomic function test results did not differ between patients with early OH and patients with transient OH, we speculated that two types of OH had a similar degree of autonomic dysfunction and may be considered a very mild form of sympathetic adrenergic failure. Approximately 17% of the patients with OD showed normal autonomic function test result. However the absence of any autonomic failure sign does not guarantee an intact autonomic function in these patients because autonomic function such as BP response show a considerable day to day and diurnal variability (Ooi et al., 1997; Weiss et al., 2002), rending it difficult to detect any autonomic failure sign including OH even in symptomatic patients. In regards to the reliability (or reproducibility) of abnormal autonomic function test result in a same individual, it is generally accepted that postganglionic sympathetic sudomotor function estimated by QSART is known to have a relatively constant test result in repeated tests (i.e., high reliability), whereas sympathoneural function estimated by tilt table and VM tests has a relatively low reliability (reproducibility) in a same individual person (Low and Benarroch, 2008). Each SI correlated with the total and each item scores of CASS. The strongest correlation was with the CASS adrenergic subscores, followed by the cardiovagal subscores and then the sudomotor subscores. Considering that orthostatic intolerance including OD usually reflects a dysfunction of the sympathetic adrenergic system, it was not surprising that the strongest correlation between the CASS subscores and each SI was found for the CASS adrenergic subscores. In addition to the CASS adrenergic subscores that are
basically related to an abnormal SI, however, the CASS cardiovagal and sudomotor subscores that seemed to be unrelated to OH were also weakly related to each SI. This probably means that although each SI usually reflects the sympathetic adrenergic failure, patients with OH may present with failures of other associated generalized autonomic systems. Thus, clinicians should evaluate the entire autonomic nervous system function in addition to the sympathetic adrenergic function estimated as CASS adrenergic subscores in patients with OD, even in the absence of other autonomic symptoms. During the VM, SIs, particularly SI 3, SI 4, and SI 5, displayed correlations with the KOGS scores, among which SI3 had strongest correlation with total and each item scores of KOGS. Our result is consistent with a previous report (Novak, 2011a) that among SIs, SI 3 had the most diagnostic value in differentiating between healthy controls and patients with sympathetic adrenergic failure. Since approximately 60% (128/217) of patients had abnormal BP responses during VM and orthostatic symptoms were correlated with SIs, VM may also be a useful tool in detecting the SAF in addition to tilt test. Furthermore, the incidence (40%) of abnormal BP responses from VM among the patients with no OH in tilt test was approximately 1.5 times higher than the incidence (27%) of OH in tilt test among patients with a normal BP response during VM. These findings suggest that VM is superior to tilt test for detection of SAF. Indeed, VM can detect mild form of SAF, whereas tilt test only detects the presence of severe generalized SAF (Sandroni et al., 1991; Low, 1993; Novak, 2011a). Therefore, both tests should be performed in the evaluation of SAF in patients with OD (Kim et al., 2013). The therapeutic intervention for treatment of autonomic dysfunction should be implemented in stages and depends on the pattern and severity of autonomic dysfunction. For example, OH as a representative dysfunction of adrenergic subscore is the most incapacitating symptom of autonomic failure. Patient education is the key cornerstone of management. Plasma volume expansion is essential to improve orthostatic tolerance, and fluid and sodium chloride intake should be increased. Most patients can be treated successfully with volume expansion or fludrocortisones or both in combination with a sympathomimetic agent.
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Fig. 2. Different patterns of sympathetic adrenergic failure during the Valsalva maneuver in a representative subject with orthostatic dizziness according to the total scores of KOGS. (A) Normal pattern. Both late phase 2 (93 mmHg) and phase 4 (95 mmHg) exceeded the baseline (77 mmHg). (B) Mild degree of sympathetic adrenergic failure. Note that the end of phase 2 (82 mmHg) failed to reach the baseline (97 mmHg), which suggests an impaired SI3. The PRT (3 s) and phase 4 (102 mmHg) were normal. (C) Moderate degree of sympathetic adrenergic failure, in which the presence of the late phase 2 was equivocal, and there is an increased difference in the MBP between the baseline and the end of phase 2 compared with the dysfunction shown in (B). The PRT is also mildly prolonged (6 s), but the phase 4 (105 mmHg) appears normal. (D) Severe degree of sympathetic adrenergic failure. Note that the recovery of the MBP at the end of phase 2 and the phase 4 overshooting are missing. The PRT is also severely prolonged (40 s). MAP = mean arterial pressure; SI = sympathetic index; PRT = pressure recovery time; KOGS = Korean version of orthostatic grading scale.
Our study has some limitations. First, because we classified patients with OD according to the patterns of autonomic dysfunctions irrespective of their underlying conditions, the possible patterns of autonomic dysfunction in OD according to underlying causes remained to be elucidated. Second, we did not attempt to compare autonomic data from patients with OD with that from a healthy control group. Thus, the relevance of a single abnormal test result should be made with caution. Further studies, including a large number of normal controls, are needed to assess the clinical implication of mild degree of autonomic dysfunction in each test. Third, some had non-sympathetic adrenergic dysfunction only such as isolated sympathetic cholinergic or parasympathetic cardiovagal dysfunctions that might theoretically be unrelated to OD, although majority (74%, 161/217) of the patients had sympathetic adrenergic dysfunction shown as abnormal tilt table and/or VM results, which are directly responsible for OD. Thus, interpretation of abnormal test result in these patients should be made with caution. A further study regarding how abnormal result in each test is closely linked to OD is needed.
Table 4 Correlations between CASS scores and sympathetic indexes during Valsalva maneuver in patients with orthostatic dizziness. CASS A SI1 SI2 SI3 SI4 SI5 (PRT) SI6 (BRSa)
C .301** .717** .530** .559** .709** .470**
S .115 .442** .308** .424** .473** .412**
Total .117 .159* .200** .149* .105 .121
.256** .632** .488** .541** .629** .476**
SI = sympathetic index; SI1 = the reduction of early phase II; SI2 = the magnitude of late phase II; SI3 = the difference in mean BP between baseline and the end of phase II; SI4 = the magnitude of phase IV; SI5 = pressure recovery time (PRT); SI6 = adrenergic baroreflex sensitivity (BRSa). CASS = composite autonomic severity score. Spearman’s correlation: * P < 0.05. ** P < 0.01.
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Fig. 3. The relationship between each SI and total scores of KOGS in patients with orthostatic dizziness. The degree of correlation with total KOGS scores was decreased in the order of SI3 > SI4 > SI5. SI = sympathetic index, KOGS = Korean version of orthostatic grading scale.
Disclosure Dr. Lee serves on the editorial boards of Frontiers in Neuro-otology, Research in Vestibular Science, and Current Medical Imaging Review. Drs. Kim and Yi report no disclosures. Acknowledgements This research was supported by the Scholar Research Grant of Keimyung University in 2013. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clinph.2013. 10.022. References Baloh RW, Kerber KA. Clinical neurophysiology of the vestibular system. 4th ed. New York: Oxford University Press; 2011. Gibbons CH, Freeman R. Delayed orthostatic hypotension: a frequent cause of orthostatic intolerance. Neurology 2006;67:28–32. Kim HA, Lee H, Park KJ, Lim JG. Autonomic dysfunction in patients with orthostatic dizziness: validation of orthostatic grading scale and comparison of Valsalva maneuver and head-up tilt testing results. J Neurol Sci 2013;325:61–6.
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Spectrum of autonomic dysfunction in orthostatic dizziness Hyun-Ah Kim, Hyon-Ah Yi, Hyung Lee ⇑ Department of Neurology, Keimyung University School of Medicine, Daegu, Republic of Korea Brain Research Institute, Keimyung University School of Medicine, Daegu, Republic of Korea
a r t i c l e
i n f o
Article history: Accepted 19 October 2013 Available online 5 November 2013 Keywords: Orthostatic dizziness Autonomic dysfunction Spectrum
h i g h l i g h t s This study investigated the frequency and detailed spectrum of autonomic dysfunction in patients
with orthostatic dizziness. Approximately 83% (180/217) of patients showed at least one abnormal autonomic testing result. We
classified orthostatic dizziness into 11 groups according to the patterns of autonomic dysfunctions. This study helps clinicians to understand the pattern and mechanism of autonomic dysfunction asso-
ciated with orthostatic dizziness.
a b s t r a c t Objective: To investigate the frequency and detailed spectrum of autonomic dysfunction in patients with orthostatic dizziness (OD). Methods: Over 20 months, 217 consecutive patients with OD as a presenting symptom of orthostatic intolerance were enrolled. The distribution and severity of autonomic dysfunction were measured by the composite autonomic severity score (CASS), which was derived from a standard autonomic function test including Finapres for recording of the beat-to-beat blood pressure. Sympathetic indexes (SIs) were calculated from the Valsalva maneuver (VM). Results: Approximately 83% of patients showed at least one abnormal autonomic testing result. We classified OD into 11 groups according to the patterns of autonomic dysfunctions. The most common pattern was generalized autonomic failure of sympathetic adrenergic and parasympathetic cardiovagal functions (n = 60). Patients with delayed OH had larger BP increases during late phase II of the VM (p = 0.04), showed greater phase IV overshoot (p = 0.04), and had a smaller pressure recovery time increase (p = 0.02) than patients with classic OH. Each SI showed the strongest correlation with the CASS adrenergic subscores. Conclusions: OD can present with a board spectrum of autonomic dysfunctions. Significance: This investigation could be useful in understanding the pattern and mechanism of autonomic dysfunction associated with OD. Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Orthostatic dizziness (OD) is a common dizzy syndrome characterized by non-vertiginous light-headedness when a patient rises to standing from a sitting or supine position (Baloh and Kerber, 2011). OD is a common complaint in not only general practice and but specialized dizziness clinics. OD is believed to be one of ⇑ Corresponding author at: Department of Neurology, Keimyung University School of Medicine, 194 Dongsan dong, Daegu 700-712, Republic of Korea. Tel.: +82 53 250 7835; fax: +82 53 250 7840. E-mail address: [email protected] (H. Lee).
the most common causes of non-vestibular dizziness (Baloh and Kerber, 2011; Radtke et al., 2011). A recent report showed that the one year and lifetime prevalence of OD were 10.9% and 12.5%, respectively (Radtke et al., 2011). Although OD usually results from orthostatic hypotension (OH) and is considered a representative sign of sympathetic autonomic dysfunction (Kim et al., 2013), the types of OH that may occur in patients with OD has not been described. Moreover, the frequency and pattern of other accompanying autonomic dysfunctions are not known. To study these problems, we prospectively investigated the autonomic test results of all the patients referred to our autonomic laboratory for evaluation of OD during a 20-month period.
1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.10.022
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2. Methods From July 2011 to February 2013, 300 patients with OD as a presenting symptom of orthostatic intolerance were initially included in this study. Most were referred to our autonomic laboratory for evaluation of OD. We defined OD as follows: (1) patients had non-vestibular dizziness including diffuse non-rotational dizziness, light-headedness, fogginess in the head, or a feeling of an impending black out and (2) dizziness that occurs only by postural changes, such as standing up from a sitting or supine position. After excluding 83 patients with OD, 217 patients were finally enrolled for this study. Among 83 excluded patients, 57 showed a flat top response during the Valsalva maneuver (VM) that was defined as an increase in the blood pressure (BP) response by at least 20 mmHg above baseline for at least 10 s, and 15 had significant arrhythmia with atrial fibrillation. Other had inadequate evaluations. A standardized battery of autonomic tests, including the headup tilt test, VM, Valsalva ratio (VR), heart rate response to deep breathing using Finometer devices (FMS, Amsterdam, The Netherlands) for recording beat-to-beat BP and heart rate (HR) response and the quantitative sudomotor axon reflex test, was performed in all the patients according to a previously validated method for the diagnosis of autonomic dysfunction (Low and Benarroch, 2008). For VM, patients were instructed to take a deep breath and blow into a syringe through a mouthpiece attached to a manometer for 15 s until expiratory pressure was reached to 40 mmHg. BP magnitude was determined for four phases, i.e., phase I, early and late phase II, phase III, and phase IV as previously described (Low, 1993; Low and Benarroch, 2008). A maximal drop in the mean blood pressure (MBP) of more than 20 mmHg during early phase II was abnormal (Novak, 2011b). Late phase II was considered abnormal if the magnitude of the end of phase II did not exceed the baseline (i.e., a negative value) (Novak, 2011b). Phase IV was considered abnormal if the magnitude of the phase IV response failed to reach the baseline (i.e., a negative value) (Novak, 2011a,b). The sympathetic indexes (SIs), including the reduction of early phase II (SI 1), magnitude of late phase II (SI 2), difference in BP between the baseline and the end of phase 2 (SI 3), magnitude of phase IV (SI 4), pressure recovery time (PRT, SI 5), and adrenergic baroreflex sensitivity index (SI 6) that have been linked to sympathetic adrenergic failure (SAF), were calculated and determined as abnormality from VM results (Novak, 2011a). The HR response was defined as the average HR difference (maximum– minimum) of the five largest consecutive responses (i.e., HRDB), and expiration/inspiration (E/I) ratio during deep breathing was calculated. The VR was derived from the maximum HR divided by the lowest HR following VM. The tilt protocol included at least 10 min in the supine position and 20 min of a tilt at 70 degrees. OH was defined by a decrease in systolic blood pressure (SBP) of at least 20 mmHg or a decrease in diastolic blood pressure (DBP) of at least 10 mmHg between supine rest for 10 min and an upright posture for 20 min (The Consensus Committee of the American Autonomic Society and the American Academy of Neurology, 1996). Classic OH was defined as a decrease in systolic BP P 20 mmHg or in diastolic BP P 10 mmHg within 3 min of tilting. Delayed OH was defined as a slow progressive decrease in SBP that occurred after 3 min of tilting. Early OH was characterized by a decrease in SBP of 40 mmHg or more, immediately (within 30 s) after tilting, with rapid normalization of the BP response after 30 s. Transient OH was defined as an orthostatic reduction in SBP of at least 20 mmHg or a decrease in DBP of at least 10 mmHg any time during the tilting except for the initial 30 s, but decreased BP response was normalised within a few minutes after the onset of orthostatic reduction. The postural orthostatic tachycardia
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syndrome (POTS) was characterized by a sustained HR increment of 30 beats per minute within 10 min of the head-up tilt in the absence of OH (Thieben et al., 2007). Postganglionic sympathetic sudomotor functions were analyzed by quantitative sudomotor axonal reflex test (QSART) at the forearm, proximal leg, and distal leg using Q-Sweat machine (WR Medical Electronics, Stillwater, MN). The volume of capsules was 0.1229 cm2, stimulation current was 2 mA, and duration of stimulation was 5 min. The sweat volume was collected for 10 min. The pattern and severity of autonomic dysfunctions in patients with OD were determined based on the composite autonomic severity score (CASS) that consisted of each subscore evaluating the sympathetic adrenergic and cholinergic, and parasympathetic cardiovagal autonomic functions (Low, 1993; Low et al., 1995, 2013). In our study, isolated POTS was not included as a possible pattern of autonomic dysfunction because it was not recognized as an abnormality in the CASS calculation. All patients were asked to complete the Korean version of the orthostatic grading scale (KOGS), which is known to be a reliable and valid tool for screening patients with OD in Korea(Kim et al., 2013). We did not exclude patients who were receiving medications with potential effects on autonomic function, such as beta-blockers, anticholinergic agents, and antihypertensive drugs because medication is also a common cause of OD. No coffee, food, or nicotine was permitted for 6 h before the study. Because this study included all consecutive patients with OD during research period, 32 patients previously reported (Kim et al., 2013) were included for completeness of the data. However, new information is added in this report. All experiments complied with the tenets of the Declaration of the Helsinki and the study was approved by the Institutional Review Board. We compared the clinical characteristics and autonomic test result data between patients with classic OH and patients with delayed OH using the independent-samples t-test for continuous variables and chi-squared test for categorical variables. The mean value ± standard deviation (SD) is displayed. A probability of p < 0.05 was considered to be statistically significant.
3. Results Our study consisted of 217 patients with a mean age of 57.1 years (SD, 16.1 years) and an even distribution of men (52%) and women. In addition to orthostatic intolerance (100%) as a presenting symptom for inclusion to this study, patients commonly complained of blurred vision (74%) weakness or tiredness (70%), and difficulty in concentration or thinking mimicking cognitive impairments (47%). The symptoms of sympathetic hyperexcitation, including tremor and chest palpitation, were noted in approximately 40% of patients. A history of syncope was noted in approximately 15% of patients. The patients’ pre-test diagnoses included 47% with hypertension, 29% with diabetes, 12% with ischemic heart disease, 11% with Parkinson’s disease, 9.7% with benign prostatic hypertrophy, 5.1% with multiple system atrophy, and 4.1% with other medical illness, including thyroid disease or systemic cancer. Thirty-seven percent (81/217) of patients had no medical illness. A total of 180 patients (83%) had at least one abnormal autonomic testing result based on an abnormality of each test in the CASS. Most (147/180, 82%) patients had abnormalities related to sympathetic adrenergic failure. If the patients with isolated POTS (n = 7) were included, 86% (187/217) of patients showed at least one abnormal autonomic result. We classified OD into 11 groups according to the patterns of autonomic impairment (Table 1).
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Table 1 Frequenciesa of autonomic dysfunctions in 217 patients with orthostatic dizziness. Frequency (n = 217) Generalized autonomic failure with sympathetic adrenergic and parasympathetic cardiovagal dysfunctions Pan-autonomic failureb Sympathetic adrenergic failure with abnormal VM only Sympathetic adrenergic failure with OH and abnormal VM only Sympathetic adrenergic failure with OH only Generalized autonomic failure with sympathetic adrenergic and cholinergic dysfunctions Parasympathetic cardiovagal failure with abnormal HRDB only Sympathetic cholinergic failure with abnormal QSART only Generalized autonomic failure with parasympathetic cardiovagal and sympathetic cholinergic dysfunctions Parasympathetic cardiovagal failure with abnormal VR and HRDB Parasympathetic cardiovagal failure with abnormal VR only
27.7% (60/217) 16.6% (36/217) 7.4% (16/217) 6.5% (14/217) 5.1% (11/217) 4.6% (10/217) 4.6% (10/217) 3.7% (8/217) 3.2% (7/217) 2.8% (6/217) 0.9% (2/217)
a
Based on composite autonomic severity score. Means both sympathetic adrenergic and cholinergic, and parasympathetic cardiovagal dysfunctions. OH = orthostatic hypotension; VM = Valsalva maneuver; HRDB = heart rate response in deep breathing; VR = Valsalva ratio. b
The three most common patterns of the autonomic dysfunction were the generalized autonomic failure (n = 60) of sympathetic adrenergic and parasympathetic cardiovagal functions followed by pan-autonomic failure (n = 36), which was defined as a complete loss of sympathetic adrenergic and cholinergic as well as parasympathetic cardiovagal functions, and isolated SAF with only an abnormal VM result (n = 16). A total of 110 patients (51%) had OH on the tilt test. We identified four patterns of OH during tilting (Table 2) as follows: 53 patients (53/110, 48%) had OH during the first 3 min of testing that remained stable or continued, progressive decline until tilt back (classic OH), 24 patients (24/110, 24%) had OH beyond 3 min after tilting that remained stable or continued, progressive decline until tilt back (delayed OH), 21 patient (21/110, 19%) had OH beyond 30 s after tilting, but decreased response normalized within a few minutes after the onset of orthostatic reduction (transient OH), and 12 patients (12/110, 11%) had an initial drop of SBP of P40 mmHg within 30 s after tilting, but OH rapidly normalized (early OH). None of patients were taking medication to control their orthostatic symptoms. Illustrative cases with different patterns OF OH during the tilting are shown in Fig. 1A–D. Patients (n = 24) with classic OH had more severe falls in SBP, DBP, and MBP during tilting than those with delayed OH. The abnormalities of SI 2–6 were more severe in patients with classic OH than in patients with delayed OH, but falls in BP during early phase II of the VM (SI 1) were not different in both groups. The total scores of KOGS and CASS, CASS adrenergic subscore, and CASS cardiovagal subscore were significantly higher in patients with classic OH than in patients with delayed OH. Other factors were not different in both groups (Table 3). There was no difference in the autonomic function test results between early and transient OH except for two parameters. The total and cardiovagal scores of KOGS were somewhat higher in
Table 2 Results of tilt table testing. Frequency (n = 217) Normal OH Classic OH Delayed OH Transient OH Early OH Neurocardiogenic syncope POTS Dizzy sensation during tilt
40.5% (88/217) 50.7% (110/217) 24.4% (53/217) 11.1% (24/217) 9.7% (21/217) 5.5% (12/217) 2.8% (6/217) 8.7% (19/217) 32.7% (71/217)
OH; orthostatic hypotension, POTS; postural tachycardia syndrome.
patients with early OH than in patients with transient OH (Supplementary Table S1). Approximately 70% (147/217) of patients had SAF that appeared as OH or abnormal VM results. Seventy-four percent (161/217) of patients showed sympathetic adrenergic dysfunction including OH, abnormal VM results, or POTS, which might be responsible for OD. Forty-nine percent (128/217) of patients showed an abnormal BP response during VM. Forty-percent (86/217) of patients showed combined abnormalities in the tilt test and VM. Only 30% (65/217) of patients had normal results on both tilt and VM. Approximately 40% (42/107) of patients with no OH during tilting showed an abnormal BP response during VM, whereas 27% (24/89) patients with normal BP response during VM showed OH during tilting. Illustrative cases with different patterns of SAF during VM, according to the total KOGS scores are shown in Fig. 2A–D. Each SI correlated with the total and each item scores of CASS. The strongest correlation was with the CASS adrenergic subscores, followed by the cardiovagal subscores, and then the sudomotor subscores. Among the six SIs, SI 2 showed the strongest correlation with the CASS adrenergic subscores. The degree of correlation between each SI and CASS adrenergic subscores decreased in the following order of SI 2 > SI 5 > SI 4 > SI 3 > SI 6 > SI 1 (Table 4). The frequencies of abnormal SIs from VM decreased in the following order of SI 2 (54%) > SI 3 (49.3%) > SI 5 (40.6%) > SI 4 (25.3%) > SI 1 (9.7%). The overall correlation analysis between the total and each item scores of KOGS and the SI 1–6 showed a partial correlation. Among the six SIs, SI 3 showed the strongest correlation with the total and each item scores of KOGS. The degree of correlation with total KOGS scores decreased in the following order of SI 3 > SI 4 > SI 5 (Fig. 3). Other SIs were not correlated to total KOGS scores. 4. Discussion To the best of our knowledge, this is the by far largest series of OD focused on the detailed spectrum of autonomic dysfunction. In our series, approximately 83% (180/217) of patients with OD showed at least one abnormal autonomic function test result. The most common pattern of autonomic dysfunction in our series was sympathetic adrenergic failure, which was diagnosed by the presence of OH or abnormal BP responses from VM that were observed in approximately 70% (147/217) of patients. Our result suggests that an abnormal VM result is also common form of autonomic dysfunction in OD. In our series, 51% (110/213) of patients with OD showed OH, which is similar to the previously reported frequency (47%) of OH (Gibbons and Freeman, 2006). In contrast to the previously reported result (Gibbons and Freeman, 2006) that two OH patterns,
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Fig. 1. Beat-to-beat blood pressure in mmHg and heart rate response in beats per minutes over 35 min (10 min supine, 20 min tilting, and 5 min re-supine) in representative subjects with classic OH (A), delayed OH (B), early OH (C), and transient OH (D). OH, orthostatic hypotension.
e.g., classic and delayed OH, are found in patients with light-headedness or dizziness as the presenting symptom, we found four patterns of OH related to OD: classic, delayed, initial, and transient OH. It has recently been recognized that delayed OH is a common pattern of OH in addition to as classic OH observed in patients who present light-headedness or presyncopal dizziness (Gibbons and Freeman, 2006). However, a previous report (Gibbons and Freeman, 2006) used BP monitoring with a measurement of 1 min interval for diagnosis of OH that cannot detect brief episodes of transient or early OH, which constituted 30% of total OH in our study. Using continuous BP monitoring to detect beat-to-beat BP response, our analysis reveals that certain patients have OH not categorized as classic or delayed OH and documented two additional patterns of OH related to OD. Greater sensitivity of screening procedure using beat-to-beat BP recording would enable the detection of these brief OH. Similar to a previous study(Gibbons and Freeman, 2006), we found that patients with classic OH had more severe falls in BP during tilting and a reduced phase IV overshoot from VM than patients with delayed OH. However, a previous report (Gibbons and Freeman, 2006) did not compare the detailed measurements of sympathetic function using SIs between patients with classic OH
and patients with delayed OH. Our results demonstrated that in addition to phase IV abnormality (SI 4), many factors that indicate sympathetic function, such as SI 2, 3, 5, 6, and CASS adrenergic subscores, were also more severely impaired in patients with classic OH than in patients with delayed OH. Unlike the previous report (Gibbons and Freeman, 2006), BP decreases during early phase II of the VM (SI 1) did not differ between the groups. Because the initial BP decrease during early phase II of the VM may depend on conditions other than sympathetic activity, such as volume status–venous capacitance (Novak, 2011a), SI 1 may less accurately reflect the functional status of sympathetic adrenergic system. The current data on the frequencies of abnormal SIs from VM, in which an abnormal SI 1 was the least among SIs, also support the contribution of non-sympathetic activity in appearance of early phase II during VM. Our study confirmed the previous notion that delayed OH is associated with milder form of sympathetic adrenergic failure. Indeed, delayed OH may be considered a mild or early stage of sympathetic adrenergic failure. Early OH observed in some patients resembles an initial OH, a frequent but underestimated cause of orthostatic intolerance (Wieling et al., 2007; Thomas et al., 2009) Similar to an initial OH, this early OH is also accompanied by a remarkable decrement of
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Table 3 Demographics and autonomic findings in patients with classic and delayed OH.
Age (y) Men (%) Baseline SBP (mmHg) Mean SBP fall during tilt Mean DBP fall during tilt Mean MBP fall during tilt HRDB E/I ratio Valsalva ratio Early phase II fall during VM (SI 1) Late phase II increase during VM (SI 2) SI 3 Phase IV overshooting during VM (SI 4) PRT (SI 5) BRSa (SI 6) KOGS total score CASS total score Adrenergic subscore Cardiovagal subscore Sudomotor subscore
Classic OH (BP fall 3 min on tilt test, n = 24)
p-Value*
62.8 ± 14.0 51% 129.5 ± 21.3 32.8 ± 19.6 11.6 ± 11.6 19.7 ± 14.0 6.1 ± 5.2 1.1 ± 0.1 1.3 ± 0.3 13.8 ± 8.9 3.5 ± 6.2 11.5 ± 12.6 4.8 ± 11.8 14.0 ± 11.5 9.8 ± 9.9 9.5 ± 4.9 4.9 ± 2.6 2.7 ± 1.3 1.7 ± 1.2 0.6 ± 1.0
60.9 ± 15.3 52% 130.2 ± 18.5 18.4 ± 8.0 5.9 ± 5.7 10.2 ± 7.8 7.5 ± 4.4 1.1 ± 0.1 1.4 ± 0.3 12.8 ± 9.0 10.1 ± 9.6 2.3 ± 14.6 11.2 ± 13.9 6.4 ± 8.8 14.6 ± 9.7 6.9 ± 3.8 3.1 ± 2.1 1.8 ± 1.3 1.4 ± 1.0 0.3 ± 0.6
.607 .99 .891 .000 .005 .000 .234 .279 .248 .664 .004 .006 .040 .002 .050 .021 .003 .006 .018 .079
OH = orthostatic hypotension; VM = Valsalva maneuver; HRDB = heart rate response in deep breathing; E/I = expiration/inspiration; PRT = pressure recovery time; KOGS = Korean version of orthostatic grading scale; CASS = composite autonomic severity score; SBP = systolic blood pressure; DBP = diastolic blood pressure; MBP = mean blood pressure; SI = sympathetic index; SI1 = the reduction of early phase II; SI2 = the magnitude of late phase II; SI3 = the difference in mean BP between baseline and the end of phase II; SI4 = the magnitude of phase IV; SI5 = pressure recovery time; SI6 = adrenergic baroreflex sensitivity (BRSa). * Chi-squared test for categorical variables and t-test for continuous variables.
SBP during the initial period of tilting, followed by a rapid and spontaneous normalization of BP. Thus, the period of hypotension is short. Unlike an initial OH that is exclusively associated with active standing up (Wieling et al., 2007; Thomas et al., 2009), early OH may occur in a condition of passive tilting, as observed in our patients. Initial OH commonly accompanies light-headedness, dizziness, and nausea as symptoms of orthostatic intolerance, whereas early OH documented during passive tilting is usually asymptomatic. Only monitoring of the beat-to-beat BP is critical for the objective documentation of both types of OH (Wieling et al., 2007; Thomas et al., 2009). Considering that nearly entire autonomic function test results did not differ between patients with early OH and patients with transient OH, we speculated that two types of OH had a similar degree of autonomic dysfunction and may be considered a very mild form of sympathetic adrenergic failure. Approximately 17% of the patients with OD showed normal autonomic function test result. However the absence of any autonomic failure sign does not guarantee an intact autonomic function in these patients because autonomic function such as BP response show a considerable day to day and diurnal variability (Ooi et al., 1997; Weiss et al., 2002), rending it difficult to detect any autonomic failure sign including OH even in symptomatic patients. In regards to the reliability (or reproducibility) of abnormal autonomic function test result in a same individual, it is generally accepted that postganglionic sympathetic sudomotor function estimated by QSART is known to have a relatively constant test result in repeated tests (i.e., high reliability), whereas sympathoneural function estimated by tilt table and VM tests has a relatively low reliability (reproducibility) in a same individual person (Low and Benarroch, 2008). Each SI correlated with the total and each item scores of CASS. The strongest correlation was with the CASS adrenergic subscores, followed by the cardiovagal subscores and then the sudomotor subscores. Considering that orthostatic intolerance including OD usually reflects a dysfunction of the sympathetic adrenergic system, it was not surprising that the strongest correlation between the CASS subscores and each SI was found for the CASS adrenergic subscores. In addition to the CASS adrenergic subscores that are
basically related to an abnormal SI, however, the CASS cardiovagal and sudomotor subscores that seemed to be unrelated to OH were also weakly related to each SI. This probably means that although each SI usually reflects the sympathetic adrenergic failure, patients with OH may present with failures of other associated generalized autonomic systems. Thus, clinicians should evaluate the entire autonomic nervous system function in addition to the sympathetic adrenergic function estimated as CASS adrenergic subscores in patients with OD, even in the absence of other autonomic symptoms. During the VM, SIs, particularly SI 3, SI 4, and SI 5, displayed correlations with the KOGS scores, among which SI3 had strongest correlation with total and each item scores of KOGS. Our result is consistent with a previous report (Novak, 2011a) that among SIs, SI 3 had the most diagnostic value in differentiating between healthy controls and patients with sympathetic adrenergic failure. Since approximately 60% (128/217) of patients had abnormal BP responses during VM and orthostatic symptoms were correlated with SIs, VM may also be a useful tool in detecting the SAF in addition to tilt test. Furthermore, the incidence (40%) of abnormal BP responses from VM among the patients with no OH in tilt test was approximately 1.5 times higher than the incidence (27%) of OH in tilt test among patients with a normal BP response during VM. These findings suggest that VM is superior to tilt test for detection of SAF. Indeed, VM can detect mild form of SAF, whereas tilt test only detects the presence of severe generalized SAF (Sandroni et al., 1991; Low, 1993; Novak, 2011a). Therefore, both tests should be performed in the evaluation of SAF in patients with OD (Kim et al., 2013). The therapeutic intervention for treatment of autonomic dysfunction should be implemented in stages and depends on the pattern and severity of autonomic dysfunction. For example, OH as a representative dysfunction of adrenergic subscore is the most incapacitating symptom of autonomic failure. Patient education is the key cornerstone of management. Plasma volume expansion is essential to improve orthostatic tolerance, and fluid and sodium chloride intake should be increased. Most patients can be treated successfully with volume expansion or fludrocortisones or both in combination with a sympathomimetic agent.
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Fig. 2. Different patterns of sympathetic adrenergic failure during the Valsalva maneuver in a representative subject with orthostatic dizziness according to the total scores of KOGS. (A) Normal pattern. Both late phase 2 (93 mmHg) and phase 4 (95 mmHg) exceeded the baseline (77 mmHg). (B) Mild degree of sympathetic adrenergic failure. Note that the end of phase 2 (82 mmHg) failed to reach the baseline (97 mmHg), which suggests an impaired SI3. The PRT (3 s) and phase 4 (102 mmHg) were normal. (C) Moderate degree of sympathetic adrenergic failure, in which the presence of the late phase 2 was equivocal, and there is an increased difference in the MBP between the baseline and the end of phase 2 compared with the dysfunction shown in (B). The PRT is also mildly prolonged (6 s), but the phase 4 (105 mmHg) appears normal. (D) Severe degree of sympathetic adrenergic failure. Note that the recovery of the MBP at the end of phase 2 and the phase 4 overshooting are missing. The PRT is also severely prolonged (40 s). MAP = mean arterial pressure; SI = sympathetic index; PRT = pressure recovery time; KOGS = Korean version of orthostatic grading scale.
Our study has some limitations. First, because we classified patients with OD according to the patterns of autonomic dysfunctions irrespective of their underlying conditions, the possible patterns of autonomic dysfunction in OD according to underlying causes remained to be elucidated. Second, we did not attempt to compare autonomic data from patients with OD with that from a healthy control group. Thus, the relevance of a single abnormal test result should be made with caution. Further studies, including a large number of normal controls, are needed to assess the clinical implication of mild degree of autonomic dysfunction in each test. Third, some had non-sympathetic adrenergic dysfunction only such as isolated sympathetic cholinergic or parasympathetic cardiovagal dysfunctions that might theoretically be unrelated to OD, although majority (74%, 161/217) of the patients had sympathetic adrenergic dysfunction shown as abnormal tilt table and/or VM results, which are directly responsible for OD. Thus, interpretation of abnormal test result in these patients should be made with caution. A further study regarding how abnormal result in each test is closely linked to OD is needed.
Table 4 Correlations between CASS scores and sympathetic indexes during Valsalva maneuver in patients with orthostatic dizziness. CASS A SI1 SI2 SI3 SI4 SI5 (PRT) SI6 (BRSa)
C .301** .717** .530** .559** .709** .470**
S .115 .442** .308** .424** .473** .412**
Total .117 .159* .200** .149* .105 .121
.256** .632** .488** .541** .629** .476**
SI = sympathetic index; SI1 = the reduction of early phase II; SI2 = the magnitude of late phase II; SI3 = the difference in mean BP between baseline and the end of phase II; SI4 = the magnitude of phase IV; SI5 = pressure recovery time (PRT); SI6 = adrenergic baroreflex sensitivity (BRSa). CASS = composite autonomic severity score. Spearman’s correlation: * P < 0.05. ** P < 0.01.
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Fig. 3. The relationship between each SI and total scores of KOGS in patients with orthostatic dizziness. The degree of correlation with total KOGS scores was decreased in the order of SI3 > SI4 > SI5. SI = sympathetic index, KOGS = Korean version of orthostatic grading scale.
Disclosure Dr. Lee serves on the editorial boards of Frontiers in Neuro-otology, Research in Vestibular Science, and Current Medical Imaging Review. Drs. Kim and Yi report no disclosures. Acknowledgements This research was supported by the Scholar Research Grant of Keimyung University in 2013. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clinph.2013. 10.022. References Baloh RW, Kerber KA. Clinical neurophysiology of the vestibular system. 4th ed. New York: Oxford University Press; 2011. Gibbons CH, Freeman R. Delayed orthostatic hypotension: a frequent cause of orthostatic intolerance. Neurology 2006;67:28–32. Kim HA, Lee H, Park KJ, Lim JG. Autonomic dysfunction in patients with orthostatic dizziness: validation of orthostatic grading scale and comparison of Valsalva maneuver and head-up tilt testing results. J Neurol Sci 2013;325:61–6.
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