Journal of the Neurological Sciences 344 (2014) 165–170
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Autonomic dysfunction in chronic persistent dizziness☆ Hyung Lee a,b, Hyun-Ah Kim a,b,⁎ a b
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: Received 3 May 2014 Received in revised form 19 June 2014 Accepted 23 June 2014 Available online 29 June 2014 Keywords: Chronic disease Dizziness Autonomic nervous system Sympathetic nervous system diseases Tilt-table test Valsalva maneuver
a b s t r a c t Objective: To investigate the autonomic dysfunction in patients with chronic persistent dizziness using standardized autonomic function tests. Methods: We prospectively recruited 18 patients with chronic persistent dizziness after excluding other causes with extensive investigations. A standardized battery of autonomic tests including the head up tilt (HUT) test, Valsalva maneuver (VM), and heart rate (HR) response to deep breathing was performed. Results: Approximately eighty percent of the patients showed at least one abnormality in autonomic tests. Two patterns of autonomic abnormality were identified: sympathetic failure, including abnormal decrease in blood pressure (BP) during HUT test or abnormal sympathetic indices related with the BP recovery during late phase II and phase IV during VM, and sympathetic hyperactivity, including abnormal increase in HR response during HUT test or an exaggerated phase IV response manifesting increased β-adrenergic tone during VM. Conclusions: Autonomic dysfunction is frequently found in patients with chronic persistent dizziness after excluding other causes with extensive investigations. Sympathetic failure or hyperactivity may be postulated as one of the possible causes of chronic persistent dizziness. Clinicians should be aware of the possibility of autonomic dysfunction in patients with chronic dizziness, even if the dizziness is not orthostatic but persistent. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Chronic dizziness is one of the most common and challenging complaints in general neurology and otology clinics. When patients complain chronic dizziness but without any history of true vertigo or any disequilibrium, a full clinical examination is warranted, including checking blood tests to rule out general medical conditions such as anemia, hypothyroidism or other endocrine conditions, diabetes or hypoglycemia, brain scans, and vestibular and autonomic function tests [1]. Although autonomic dysfunction is a known cause of non vertiginous dizziness, dizziness related to autonomic dysfunction is characterized by not chronic persistent but occasional recurrent non-vertiginous dizziness, light-headedness, or fogginess in the head, which is typically developed by orthostatic challenges such as arising from a recumbent posture or standing for an extended period [2]. To the best of our knowledge, there has been no systematic report on the characteristic of autonomic dysfunction in patients with chronic persistent (not orthostatic) dizziness who had no other identifiable causes using a standardized battery of ☆ Competing interests: Dr. Kim reports no disclosures.Dr. Lee serves on the editorial boards of the Research in Vestibular Science, Frontiers in Neuro-otology, and Current Medical Imaging Review. ⁎ Corresponding author at: Department of Neurology, Keimyung University School of Medicine, 56 Dalseong-ro, Jung-gu, Daegu 700-712, Republic of Korea. Tel.: +82 53 250 7475; fax: +82 53 250 7840. E-mail address: [email protected] (H.-A. Kim).
http://dx.doi.org/10.1016/j.jns.2014.06.048 0022-510X/© 2014 Elsevier B.V. All rights reserved.
autonomic function test. The aim of the present study was to investigate the frequency and pattern of autonomic abnormalities using standardized autonomic function tests in patients with chronic persistent dizziness after excluding other causes with extensive investigations. 2. Methods From October 2011 to September 2012, we prospectively investigated patients with chronic persistent dizziness at the Dizziness Clinic of Keimyung University Dongsan Medical Center. We included patients with chronic persistent dizziness of an unknown cause as the following: (1) patients who presented with spontaneous (not positional) non-vertiginous dizziness lasting at least 3 months, (2) patients who felt dizziness continuously even if its severity can be changed, and (3) patients who had normal video-oculography results and brain MRI or CT. We excluded (1) patients with a typical history of dizziness evoked by orthostatic position because the autonomic dysfunction is easily suspected as a cause of dizziness in these patients, (2) patients who had identifiable neurological, psychiatric, cardiac, or other medical conditions that could potentially cause chronic dizziness, including Parkinson's disease, multiple system atrophy, peripheral polyneuropathy, stroke, migraine, syncope, head trauma, active psychiatric disorders, cardiac diseases, diabetes, hypertension, thyroid disease, alcoholism, or other medication history, and (3) patients with a recent history of diarrhea, vomiting, dehydration, or infection that could potentially lead to a transient deterioration of autonomic dysfunction.
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H. Lee, H.-A. Kim / Journal of the Neurological Sciences 344 (2014) 165–170
All of the patients underwent routine medical evaluations, including history taking, physical and neurological examination, routine blood sampling, detailed neurological examinations, video-oculography, and brain MRI or CT. The patients received a standardized psychiatric evaluation using semi-structured diagnostic interviews that systematically checked the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [3] and the revised version of the Symptom Check List-90 (SCL-90R) [4] to exclude any acute psychiatric disorders. The patients with T-score higher than 60 on each dimension were considered to have an appreciable level of symptoms [5] and are excluded in this study. During the study period, 636 patients visited our dizziness clinic. Among these patients, 18 patients met our strict inclusion and exclusion criteria. A standardized battery of autonomic tests, including the head up tilt (HUT) test, Valsalva maneuver (VM), and deep breathing test using Finometer devices (FMS, Amsterdam, Netherlands) to record the beat-to-beat blood pressure (BP) and heart rate (HR) response was performed according to a previously validated method for the diagnosis of autonomic dysfunction [2,6]. Sympathetic functions were measured using the BP responses to both the VM and HUT test. VM was performed with expiratory pressure equal to 40 mmHg for 15 seconds by blowing through the mouthpiece attached to a manometer. The tilt protocol included 10 minutes in the supine position and at least 20 minutes of a tilt at 70 degrees if it was considered safe. Beat-to-beat BP and heart rate response were measured noninvasively using the Finometer device (Finapres Medical Systems BV, Amsterdam, The Netherlands). Sympathetic indices (SIs) indicating BP change during VM, including reduction of early phase II (SI1), magnitude of late phase II (SI2), difference in mean BP (MBP) between baseline and the end of phase II (SI3), magnitude of phase IV (SI4), and pressure recovery time (PRT, SI5), were also calculated from the VM results [7,8]. A “flat-top” response, which indicated that the MBP did not fall below baseline levels during phase II, was regarded as an incomplete study (Fig. 1). The cardiovagal function was evaluated by the expiration (E): inspiration (I) ratio and the HR change to deep breathing (i.e., HRDB), Valsalva ratio (VR) during VM, and HR responses during the recovery phase of VM and the 5 minutes immediately after the HUT test. The control group consisted of 40 healthy age-matched (mean ± SD = 49.2 ± 11.2 years; range 26 to 70 years) and gender-matched (19 men, 21 women) volunteers who demonstrated no dizziness and had normal neurological examinations or medication histories that would potentially affect the autonomic nervous. None of the controls had clinically significant illness system. Autonomic data obtained from the patients were compared to control subjects. The tests were considered as abnormal if they were ± 2 SDs outside of the average value (Table 1). One-way analysis of variance (ANOVA) was used to determine the overall differences between subject groups, including controls. The
post hoc Duncan test was used for pairwise comparisons if the ANOVA showed an overall significance. Independent t-test was used to compare age between patient groups. We also used chi-square test to compare sex differences between patient groups. The significance level was set to p b 0.05. Statistical analysis was performed using SPSS version 18.0 (SPSS, Chicago, IL) for Windows. All of the experiments complied with the tenets of the Declaration of Helsinki, and the study protocol was also reviewed and approved by Keimyung University Institutional Review Board. 3. Results We identified 18 patients (9 men) with chronic persistent dizziness who had no abnormal result in extensive investigations to identify the cause of chronic dizziness. These patients represented 2.8% (18/636) of all patients with dizziness who visited our dizziness clinic during the 12-month study period. The average age of the patients was 46.7 (SD = 10.0) years with a range from 32 to 73 years. The mean duration of the symptoms in our patients was 6.3 (SD = 2.9) years. Seventy-eight percent (14/18) of the patients showed at least one abnormality in autonomic function tests: abnormal increase in HR response in the HUT test (6/18, 33%), abnormal SIs (5/18, 28%), increased VR (5/18, 28%), abnormal decrease in BP response (4/18, 22%), decreased E:I ratio and HRDB (1/18, 6%), and abnormal decrease in HR during the recovery phase of VM (1/18, 6%). In 12 (67%) patients, two patterns of autonomic abnormality were identified: decreased sympathetic responses (n = 5), including abnormal decrease in BP response during the HUT test, increase in PRT (SI5), decrease in the magnitude of late phase II (SI2), or decrease in the difference in MBP between baseline and the end of phase II (SI3) during VM (i.e., sympathetic failure group); and sympathetic hyperactivity (n = 7), including an exaggerated magnitude of phase IV (SI4) during the VM or abnormal increase in HR response during the HUT test (i.e., sympathetic hyperactivity group). Between the two groups, there was no difference in terms of gender (men, 40% vs. 43%); however, the sympathetic failure group consisted of older patients compared with the sympathetic hyperactivity group (51.8 ± 5.7 vs. 38.4 ± 4.9 years, p = 0.001). The sympathetic failure group exhibited significantly larger maximum and mean reductions in systolic BP (SBP) and diastolic BP (DBP) and a significantly larger maximum reduction in MBP in the HUT test compared to control subjects or the sympathetic hyperactivity group. In contrast, the sympathetic hyperactivity group exhibited significantly larger maximum and mean increases in HR in the HUT test compared to control subjects or the sympathetic failure group. In the VM, the SI2 and 3 were significantly lower in the sympathetic failure group compared to controls or the sympathetic hyperactivity group. In addition, the VR was increased in the sympathetic hyperactivity group compared to controls or the sympathetic failure group. Comparison of autonomic parameters between patients with sympathetic dysregulation (i.e., sympathetic failure or
Fig. 1. Example of a “flat-top” response. Flat top response refers that the mean blood pressure does not fall below baseline levels during phase II and is regarded as an incomplete study. SBP, systolic blood pressure; MBP, mean blood pressure; DBP, diastolic blood pressure.
H. Lee, H.-A. Kim / Journal of the Neurological Sciences 344 (2014) 165–170
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Table 1 Patterns of autonomic abnormalities in patients with chronic persistent dizziness. Patient/sex/ age, yr
Head up tilt test
1/F/54 2/F/42 3/F/55 4/M/56 5/M/52 6/F/41 7/M/35 8/F/40 9/F/38 10/F/36 11/M/32 12/M/47 13/F/41 14/M/73 15/F/50 16/M/52 17/M/54 18/M/43
Abnormal decrease in BPBP Abnormal decrease in BP Abnormal decrease in BP Abnormal decrease in BP Normal Abnormal increase in HR Abnormal increase in HR Abnormal increase in HR Abnormal increase in HR Abnormal increase in HR Abnormal increase in HR Normal Normal Normal Normal Normal Normal Normal
Valsalva maneuver
Cardiovagal
Final diagnosis
Normal Normal Normal Normal Normal Normal Increased VR Increased VR Abnormal decrease in HR during recovery phase of VM Normal Increased VR Increased VR Increased VR decreased E:I ratio and HRDB Normal Normal Normal Normal
Sympathetic failure, incomplete study Sympathetic failure Sympathetic failure Sympathetic failure Sympathetic failure Sympathetic hyperactivity Sympathetic hyperactivity Sympathetic hyperactivity Mixed response Sympathetic hyperactivity Sympathetic hyperactivity Sympathetic hyperactivity ? Cardiovagal dysfunction Normal Normal Normal Incomplete study
BP response Flat top response Normal Reduced SI2, and SI3 Reduced SI3 Reduced SI3 and increased PRT (SI5) Normal Normal Normal Normal Exaggerated SI4 Normal Exaggerated SI4 Normal Normal Normal Normal Normal Flat top response
BP, blood pressure; HR, heart rate; VR, valsalva ratio; HRDB, heart rate to deep breathing; SI, sympathetic indexes; PRT, pressure recovery time; VM, valsalva maneuver. Normative data from controls: maximum fall in SBP during head up tilt test b 23.7 mmHg, maximum fall in DBP during head up tilt test b 12 mmHg, maximum HR increase during head up tilt test b 27.1, SI1 b 19.9, SI2 N 3.4, SI3 N −4.2, −2.7 b SI4 b 46.2, PRT (SI5) b 3.1, E:I ratio N 1.4, HRDB N 5.1, 1.2 b Valsalva ratio b 2.2, HR during recovery phase of VM N 77% of baseline HR.
sympathetic hyperactivity) and normal controls was summarized in Table 2. Four patients (patients 1–4) had abnormal decrease in BP response within 3 minutes, which persisted during the entire period of HUT test in 3 patients (patients 2, 3, and 4), and abnormal decrease in BP response was transient in 1 patient (patient 1) for 5 minutes (range of BP decrease; 27–34 mmHg). During the VM, two patients (patients 3 and 4) with abnormal decrease in BP response during HUT test also demonstrated abnormal SI3 and/or SI2 compared to controls. Patient 5 only showed reduced SI3 and PRT (SI5) compared to controls.
Representative cases with persistent abnormal BP decrease during the HUT test in patient 3 and abnormal SIs in patient 5 are shown in Fig. 2A and C, respectively. Six patients (patients 6–11) exhibited significantly elevated HR during the HUT test compared to controls. Two patients (patients 10 and 12) showed exaggerated SI4 compared to controls. Patients with abnormal increase in HR during the HUT test or exaggerated SI4 during the VM (patients 7, 8, 11, and 12) also demonstrated increased VR compared to controls. Illustrative patient cases with abnormal increase in HR response during the HUT test in patient 7 and abnormal VR results in patient 12 are shown in Fig. 3A and B, respectively. Patient
Table 2 Autonomic parameters in patients with sympathetic dysregulation and normal controls. Sympathetic failure
Head up tilt test SBP, baseline, mmHg Maximum fall in SBP, mmHg Mean fall in SBP, mmHg MBP, baseline, mmHg Maximum fall in MBP, mmHg Mean fall in MBP, mmHg DBP, baseline, mmHg Maximum fall in DBP, mmHg Mean fall in DBP, mmHg HR, baseline Maximum increase in HR Mean increase in HR Valsalva maneuver MBP, baseline, mmHg MBP of phase 2E end, mmHg MBP of phase 2 L end, mmHg MBP of phase 4, mmHg SI1 SI2 SI3 SI4 PRT (SI5), sec Cardiovagal test E:I ratio HRDB Valsalva ratio
Sympathetic hyperactivity
Controls
Mean
SD
Mean
SD
Mean
SD
124.8 −26.6a −12.4a 90.6 −18.4a −5.4 69.6 −13.8a −1.6a 56.0 18.6 12.6
17.6 10.2 14.4 13.4 6.0 8.5 10.1 6.8 4.8 4.1 7.7 6.1
112.0 −12.0 −3.1 84.0 −8.3 0.6 64.1 −3.6 3.6 65.0 26.9a 19.7a
14.1 4.9 8.1 9.6 4.2 6.4 6.9 3.7 4.8 8.9 4.1 3.8
117.4 −12.5 −0.6 86.0 −7.3 1.5 64.8 −3.2 3.3 68.7 15.8 11.0
15.2 5.6 6.5 10.5 4.6 4.0 7.6 4.4 3.8 7.8 5.7 5.4
98.0 87.7 90.7 110.7 10.3 3.0a −7.3a 12.7 2.3
16.5 19.4 25.7 22.0 10.1 8.2 11.2 9.7 1.5
90.3 80.6 104.1 120.1 9.7 23.6 13.9 29.9 1.1
11.2 10.7 15.7 25.4 10.9 13.9 8.0 17.2 0.4
87.5 78.0 98.5 109.3 8.6 21.0 11.0 21.7 1.7
9.9 10.9 14.4 17.4 5.7 8.8 7.6 12.2 0.7
1.2 10.1 1.6
0.1 4.0 0.1
0.1 5.3 0.3
1.2 15.0 1.7
0.1 4.9 0.2
1.2 12.0 2.1a
SBP, systolic blood pressure; MBP, mean blood pressure; DBP, diastolic blood pressure; HR, heart rate; E, early; L, late; SI, sympathetic index; PRT, pressure recovery time; HRDB, HR change to deep breathing. a Significant difference as compared to other groups.
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Fig. 2. (A) The head up tilt test in patients with a sympathetic failure. There was a decrease of systolic blood pressure of up to 30 mmHg within 3 minutes after the head up tilt test that is persisted during the entire period of head up tilt test, consistent with classic orthostatic hypotension (patient 3). (B) Valsalva maneuver in healthy subject. Late phase 2 is over the resting MBP level and PRT (SI5) is very short less than 4 seconds. (C) Valsalva maneuver in patient 5 with a sympathetic failure. Late phase 2 is far less than the resting MBP level, and PRT (SI5) is prolonged about 10 seconds. BP, blood pressure; SBP, systolic blood pressure; MBP, mean blood pressure; DBP, diastolic blood pressure; PRT, pressure recovery time; IIE, early phase II; IIL, late phase II.
13 only presented with increased VR. There was no hypervagal response after the HUT test; however, one patient (patient 9) presented with abnormal decrease in HR response after the VM (i.e., hypervagal response). One patient (patient 14) exhibited a decreased cardiovagal response with lower E:I ratio and HRDB. Two patients (patients 1 and 18) showed “flattop” responses in the VM. Three patients (patients 15–17) had normal responses to all of the autonomic function tests (Table 1). 4. Discussion The key finding of our study was that the frequency of autonomic dysfunction was very high in patients with chronic persistent dizziness after excluding of other causes with extensive investigations. In this study, approximately 80% of the patients with chronic persistent dizziness of an unknown origin exhibited at least one autonomic abnormality. Another important finding was that two opposing mechanisms of autonomic dysfunction were related with chronic persistent dizziness: sympathetic failure, which included abnormal decrease in BP response during the HUT test or abnormal SIs in the VM; and sympathetic hyperactivity, which included an abnormal increase in HR response during the HUT test or exaggerated SI4 in the VM. There have been some previous studies [9,10] about autonomic dysfunction in patients with chronic dizziness. In the report [9] using the HUT test, various patterns of autonomic dysfunction were reported, such as neutrally mediated syncope, postural tachycardia syndrome (POTS), and a mildly abnormal heart rate elevation with diastolic hypotension in patients with chronic dizziness. One third (6/18) of our patients also showed abnormal HR increase (compared to controls) during the HUT test, and HR response during the tilting in three patients was compatible with POTS. The POTS is characterized by a sustained HR increase of 30 beats per minute within 10 minutes of the HUT test [11]. Indeed, POTS is a representative syndrome related to orthostatic intolerance [12]. However, it has also been proposed that POTS may contribute to non-orthostatic symptoms, which are not triggered by orthostatic stress, such as gastrointestinal discomfort, urinary symptoms, sleep disturbances, pain, fatigue, or chronic persistent dizziness [11,13]. But,
there was no prior report emphasizing the clinical relevance of POTS as a cause of chronic persistent (not orthostatic) dizziness. Apart from abnormal increased HR during the HUT test speaking for a sympathetic hyperactivity, abnormal BP fall (compared to controls) during the HUT test and SI abnormalities during the VM are also suggested as a cause of chronic persistent dizziness in our study. Abnormal BP decrease during the HUT test of our patients were compatible with orthostatic hypotension (OH), which was defined as a decrease in SBP of at least 20 mmHg or a decrease in DBP of at least 10 mmHg [14]. A number of patients with OH who exhibit none of the typical severe symptoms such as blackouts or near-fainting spells are usually categorized as asymptomatic [15]. However, most patients with asymptomatic OH actually may have subtle symptoms, which are profoundly exacerbated by routine physical activities such as eating, showering, and low-intensity exercise [15]. Our patients performed not only the HUT test but the VM, which was essential for the evaluation of adrenergic autonomic dysfunction [16]. Seventeen percent (3/18) of patients showed reduced SI2 and/or SI3 in VM. Both SI2 and SI3 are calculated based on the BP recovery from the BP fall of the early phase of phase II. The baroreflex arrests the BP fall during the VM and forms the late phase II by an increase in both efferent sympathetic discharge to muscle and plasma norepinephrine concentration [7]. Reduced SI2 and/or SI3 reflecting the failure of vasoconstrictor response are probably the most sensitive trackers of total peripheral adrenergic activation [17]. PRT (SI5) is calculated from the recovery time from BP fall after phase III and is also a valuable index of adrenergic failure [8]. In contrast, exaggerated SI4 which is observed in two patients, manifests increased β-adrenergic tone, which may lead to increased HR response as in patients with POTS. It is very interesting that two opposite abnormalities, sympathetic failure and hyperactivity, can be related with chronic dizziness. We speculated that the disruption in the balance in the sympathetic adrenergic system directed to either overactivity or hypofunction can induce cerebral hypoperfusion, which ultimately causes dizziness symptoms.
H. Lee, H.-A. Kim / Journal of the Neurological Sciences 344 (2014) 165–170
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Fig. 3. Blood pressure and heart rate response during the head up tilt test and Valsalva maneuver in patients with a sympathetic hyperactivity. (A) Increased heart rate over 30 beats within 10 minutes without any change of blood pressure during the head up tilt test in patient 7 is consistent with POTS. (B) Exaggerated increase of MBP in phase IV and increased Valsalva ratio during Valsalva maneuver in patient 12. POTS, postural orthostatic tachycardia syndrome; BP, blood pressure; HR, heart rate; SBP, systolic blood pressure; MBP, mean blood pressure; DBP, diastolic blood pressure.
Patient 9 exhibited increased HR during the HUT test and a hypervagal response during the recovery phase of the VM. Sympathetic hyperactivity and hypervagal response (i.e., mixed response) have been previously reported in patients with dizziness of nonvestibular origin [15]. Because higher VR compared to controls was mostly identified in patients with increased HR in the HUT test, we proposed that a higher VR itself might also be considered as a marker of sympathetic hyperactivity. In our study, approximately 2.8% of patients with dizziness who were referred to our dizziness clinic during the 12-month study period had chronic persistent dizziness due to autonomic dysfunction. This was higher than the prevalence (0. 4–1.5%) of purely autonomic dizziness described in previous reports [9,10]. Discordance between our study and previous reports [9,10] could be partly explained in methodological differences. First, we used continuous BP monitoring to detect beat-to-beat BP recording, whereas a previous study [9] used BP monitoring with measurements of one-minute intervals that could not detect brief episodes of transient OH or increased HR response. Second, previous reports [9,10] did not include the VM, which is an essential tool for the evaluation of adrenergic sympathetic dysfunction. The abnormal SIs from the VM can reflect the mild to moderate
adrenergic failure [8]. A higher sensitivity in the screening procedure using beat-to-beat BP recordings and the VM enables the detection of mild autonomic dysfunction and in turn, improves the potential for detecting autonomic dysfunction. The major limitation of our study was the small sample size. The strict exclusion in our study was necessary for excluding other causes of subjective dizziness, but it also diminished the sample size and limited the participation of aged people who tended to have various other disorders. Thus, future studies should be performed with a large sample size. In conclusion, autonomic dysfunction is frequently observed in patients with chronic persistent dizziness of an unknown cause. Dysautonomia with sympathetic failure or hyperactivity might contribute to chronic persistent dizziness. Thus, clinicians should be aware of the possibility of autonomic dysfunction in patients with chronic dizziness, even if the dizziness is not orthostatic but persistent. References [1] Bronstein AM, Lempert T, Seemungal BM. Chronic dizziness: a practical approach. Pract Neurol 2010;10:129–39. [2] Bannister R, Mathias CJ. Autonomic failure: a textbook of clinical disorders of the autonomic nervous system. 4th ed. Oxford; New York: Oxford University Press; 1999.
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[3] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, DSM-IV. 4th ed. Washington, DC: American Psychiatric Association; 1994. [4] Derogatis LR, Unger R. Symptom Checklist-90-Revised. The Corsini Encyclopedia of Psychology. John Wiley & Sons, Inc.; 2010 [5] Derogatis LR, Cleary PA. Factorial invariance across gender for the primary symptom dimensions of the SCL-90. Br J Soc Clin Psychol 1977;16:347–56. [6] Low PA, Tomalia VA, Park KJ. Autonomic function tests: some clinical applications. J Clin Neurol 2013;9:1–8. [7] Vogel ER, Sandroni P, Low PA. Blood pressure recovery from Valsalva maneuver in patients with autonomic failure. Neurology 2005;65:1533–7. [8] Novak P. Assessment of sympathetic index from the Valsalva maneuver. Neurology 2011;76:2010–6. [9] Staab JP, Ruckenstein MJ. Autonomic nervous system function in chronic dizziness. Otol Neurotol 2007;28:854–9. [10] Staab JP, Ruckenstein MJ. Expanding the differential diagnosis of chronic dizziness. Arch Otolaryngol Head Neck Surg 2007;133:170–6.
[11] Low PA, Sandroni P, Joyner M, Shen WK. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol 2009;20:352–8. [12] Thieben MJ, Sandroni P, Sletten DM, Benrud-Larson LM, Fealey RD, Vernino S, et al. Postural orthostatic tachycardia syndrome: the Mayo clinic experience. Mayo Clin Proc 2007;82:308–13. [13] Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc 2012;87:1214–25. [14] Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011;21:69–72. [15] Low PA, Benarroch EE. Clinical autonomic disorders. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2008. [16] 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. [17] Sandroni P, Benarroch EE, Low PA. Pharmacological dissection of components of the Valsalva maneuver in adrenergic failure. J Appl Physiol 1991;71:1563–7.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Autonomic dysfunction in chronic persistent dizziness☆ Hyung Lee a,b, Hyun-Ah Kim a,b,⁎ a b
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: Received 3 May 2014 Received in revised form 19 June 2014 Accepted 23 June 2014 Available online 29 June 2014 Keywords: Chronic disease Dizziness Autonomic nervous system Sympathetic nervous system diseases Tilt-table test Valsalva maneuver
a b s t r a c t Objective: To investigate the autonomic dysfunction in patients with chronic persistent dizziness using standardized autonomic function tests. Methods: We prospectively recruited 18 patients with chronic persistent dizziness after excluding other causes with extensive investigations. A standardized battery of autonomic tests including the head up tilt (HUT) test, Valsalva maneuver (VM), and heart rate (HR) response to deep breathing was performed. Results: Approximately eighty percent of the patients showed at least one abnormality in autonomic tests. Two patterns of autonomic abnormality were identified: sympathetic failure, including abnormal decrease in blood pressure (BP) during HUT test or abnormal sympathetic indices related with the BP recovery during late phase II and phase IV during VM, and sympathetic hyperactivity, including abnormal increase in HR response during HUT test or an exaggerated phase IV response manifesting increased β-adrenergic tone during VM. Conclusions: Autonomic dysfunction is frequently found in patients with chronic persistent dizziness after excluding other causes with extensive investigations. Sympathetic failure or hyperactivity may be postulated as one of the possible causes of chronic persistent dizziness. Clinicians should be aware of the possibility of autonomic dysfunction in patients with chronic dizziness, even if the dizziness is not orthostatic but persistent. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Chronic dizziness is one of the most common and challenging complaints in general neurology and otology clinics. When patients complain chronic dizziness but without any history of true vertigo or any disequilibrium, a full clinical examination is warranted, including checking blood tests to rule out general medical conditions such as anemia, hypothyroidism or other endocrine conditions, diabetes or hypoglycemia, brain scans, and vestibular and autonomic function tests [1]. Although autonomic dysfunction is a known cause of non vertiginous dizziness, dizziness related to autonomic dysfunction is characterized by not chronic persistent but occasional recurrent non-vertiginous dizziness, light-headedness, or fogginess in the head, which is typically developed by orthostatic challenges such as arising from a recumbent posture or standing for an extended period [2]. To the best of our knowledge, there has been no systematic report on the characteristic of autonomic dysfunction in patients with chronic persistent (not orthostatic) dizziness who had no other identifiable causes using a standardized battery of ☆ Competing interests: Dr. Kim reports no disclosures.Dr. Lee serves on the editorial boards of the Research in Vestibular Science, Frontiers in Neuro-otology, and Current Medical Imaging Review. ⁎ Corresponding author at: Department of Neurology, Keimyung University School of Medicine, 56 Dalseong-ro, Jung-gu, Daegu 700-712, Republic of Korea. Tel.: +82 53 250 7475; fax: +82 53 250 7840. E-mail address: [email protected] (H.-A. Kim).
http://dx.doi.org/10.1016/j.jns.2014.06.048 0022-510X/© 2014 Elsevier B.V. All rights reserved.
autonomic function test. The aim of the present study was to investigate the frequency and pattern of autonomic abnormalities using standardized autonomic function tests in patients with chronic persistent dizziness after excluding other causes with extensive investigations. 2. Methods From October 2011 to September 2012, we prospectively investigated patients with chronic persistent dizziness at the Dizziness Clinic of Keimyung University Dongsan Medical Center. We included patients with chronic persistent dizziness of an unknown cause as the following: (1) patients who presented with spontaneous (not positional) non-vertiginous dizziness lasting at least 3 months, (2) patients who felt dizziness continuously even if its severity can be changed, and (3) patients who had normal video-oculography results and brain MRI or CT. We excluded (1) patients with a typical history of dizziness evoked by orthostatic position because the autonomic dysfunction is easily suspected as a cause of dizziness in these patients, (2) patients who had identifiable neurological, psychiatric, cardiac, or other medical conditions that could potentially cause chronic dizziness, including Parkinson's disease, multiple system atrophy, peripheral polyneuropathy, stroke, migraine, syncope, head trauma, active psychiatric disorders, cardiac diseases, diabetes, hypertension, thyroid disease, alcoholism, or other medication history, and (3) patients with a recent history of diarrhea, vomiting, dehydration, or infection that could potentially lead to a transient deterioration of autonomic dysfunction.
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All of the patients underwent routine medical evaluations, including history taking, physical and neurological examination, routine blood sampling, detailed neurological examinations, video-oculography, and brain MRI or CT. The patients received a standardized psychiatric evaluation using semi-structured diagnostic interviews that systematically checked the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [3] and the revised version of the Symptom Check List-90 (SCL-90R) [4] to exclude any acute psychiatric disorders. The patients with T-score higher than 60 on each dimension were considered to have an appreciable level of symptoms [5] and are excluded in this study. During the study period, 636 patients visited our dizziness clinic. Among these patients, 18 patients met our strict inclusion and exclusion criteria. A standardized battery of autonomic tests, including the head up tilt (HUT) test, Valsalva maneuver (VM), and deep breathing test using Finometer devices (FMS, Amsterdam, Netherlands) to record the beat-to-beat blood pressure (BP) and heart rate (HR) response was performed according to a previously validated method for the diagnosis of autonomic dysfunction [2,6]. Sympathetic functions were measured using the BP responses to both the VM and HUT test. VM was performed with expiratory pressure equal to 40 mmHg for 15 seconds by blowing through the mouthpiece attached to a manometer. The tilt protocol included 10 minutes in the supine position and at least 20 minutes of a tilt at 70 degrees if it was considered safe. Beat-to-beat BP and heart rate response were measured noninvasively using the Finometer device (Finapres Medical Systems BV, Amsterdam, The Netherlands). Sympathetic indices (SIs) indicating BP change during VM, including reduction of early phase II (SI1), magnitude of late phase II (SI2), difference in mean BP (MBP) between baseline and the end of phase II (SI3), magnitude of phase IV (SI4), and pressure recovery time (PRT, SI5), were also calculated from the VM results [7,8]. A “flat-top” response, which indicated that the MBP did not fall below baseline levels during phase II, was regarded as an incomplete study (Fig. 1). The cardiovagal function was evaluated by the expiration (E): inspiration (I) ratio and the HR change to deep breathing (i.e., HRDB), Valsalva ratio (VR) during VM, and HR responses during the recovery phase of VM and the 5 minutes immediately after the HUT test. The control group consisted of 40 healthy age-matched (mean ± SD = 49.2 ± 11.2 years; range 26 to 70 years) and gender-matched (19 men, 21 women) volunteers who demonstrated no dizziness and had normal neurological examinations or medication histories that would potentially affect the autonomic nervous. None of the controls had clinically significant illness system. Autonomic data obtained from the patients were compared to control subjects. The tests were considered as abnormal if they were ± 2 SDs outside of the average value (Table 1). One-way analysis of variance (ANOVA) was used to determine the overall differences between subject groups, including controls. The
post hoc Duncan test was used for pairwise comparisons if the ANOVA showed an overall significance. Independent t-test was used to compare age between patient groups. We also used chi-square test to compare sex differences between patient groups. The significance level was set to p b 0.05. Statistical analysis was performed using SPSS version 18.0 (SPSS, Chicago, IL) for Windows. All of the experiments complied with the tenets of the Declaration of Helsinki, and the study protocol was also reviewed and approved by Keimyung University Institutional Review Board. 3. Results We identified 18 patients (9 men) with chronic persistent dizziness who had no abnormal result in extensive investigations to identify the cause of chronic dizziness. These patients represented 2.8% (18/636) of all patients with dizziness who visited our dizziness clinic during the 12-month study period. The average age of the patients was 46.7 (SD = 10.0) years with a range from 32 to 73 years. The mean duration of the symptoms in our patients was 6.3 (SD = 2.9) years. Seventy-eight percent (14/18) of the patients showed at least one abnormality in autonomic function tests: abnormal increase in HR response in the HUT test (6/18, 33%), abnormal SIs (5/18, 28%), increased VR (5/18, 28%), abnormal decrease in BP response (4/18, 22%), decreased E:I ratio and HRDB (1/18, 6%), and abnormal decrease in HR during the recovery phase of VM (1/18, 6%). In 12 (67%) patients, two patterns of autonomic abnormality were identified: decreased sympathetic responses (n = 5), including abnormal decrease in BP response during the HUT test, increase in PRT (SI5), decrease in the magnitude of late phase II (SI2), or decrease in the difference in MBP between baseline and the end of phase II (SI3) during VM (i.e., sympathetic failure group); and sympathetic hyperactivity (n = 7), including an exaggerated magnitude of phase IV (SI4) during the VM or abnormal increase in HR response during the HUT test (i.e., sympathetic hyperactivity group). Between the two groups, there was no difference in terms of gender (men, 40% vs. 43%); however, the sympathetic failure group consisted of older patients compared with the sympathetic hyperactivity group (51.8 ± 5.7 vs. 38.4 ± 4.9 years, p = 0.001). The sympathetic failure group exhibited significantly larger maximum and mean reductions in systolic BP (SBP) and diastolic BP (DBP) and a significantly larger maximum reduction in MBP in the HUT test compared to control subjects or the sympathetic hyperactivity group. In contrast, the sympathetic hyperactivity group exhibited significantly larger maximum and mean increases in HR in the HUT test compared to control subjects or the sympathetic failure group. In the VM, the SI2 and 3 were significantly lower in the sympathetic failure group compared to controls or the sympathetic hyperactivity group. In addition, the VR was increased in the sympathetic hyperactivity group compared to controls or the sympathetic failure group. Comparison of autonomic parameters between patients with sympathetic dysregulation (i.e., sympathetic failure or
Fig. 1. Example of a “flat-top” response. Flat top response refers that the mean blood pressure does not fall below baseline levels during phase II and is regarded as an incomplete study. SBP, systolic blood pressure; MBP, mean blood pressure; DBP, diastolic blood pressure.
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Table 1 Patterns of autonomic abnormalities in patients with chronic persistent dizziness. Patient/sex/ age, yr
Head up tilt test
1/F/54 2/F/42 3/F/55 4/M/56 5/M/52 6/F/41 7/M/35 8/F/40 9/F/38 10/F/36 11/M/32 12/M/47 13/F/41 14/M/73 15/F/50 16/M/52 17/M/54 18/M/43
Abnormal decrease in BPBP Abnormal decrease in BP Abnormal decrease in BP Abnormal decrease in BP Normal Abnormal increase in HR Abnormal increase in HR Abnormal increase in HR Abnormal increase in HR Abnormal increase in HR Abnormal increase in HR Normal Normal Normal Normal Normal Normal Normal
Valsalva maneuver
Cardiovagal
Final diagnosis
Normal Normal Normal Normal Normal Normal Increased VR Increased VR Abnormal decrease in HR during recovery phase of VM Normal Increased VR Increased VR Increased VR decreased E:I ratio and HRDB Normal Normal Normal Normal
Sympathetic failure, incomplete study Sympathetic failure Sympathetic failure Sympathetic failure Sympathetic failure Sympathetic hyperactivity Sympathetic hyperactivity Sympathetic hyperactivity Mixed response Sympathetic hyperactivity Sympathetic hyperactivity Sympathetic hyperactivity ? Cardiovagal dysfunction Normal Normal Normal Incomplete study
BP response Flat top response Normal Reduced SI2, and SI3 Reduced SI3 Reduced SI3 and increased PRT (SI5) Normal Normal Normal Normal Exaggerated SI4 Normal Exaggerated SI4 Normal Normal Normal Normal Normal Flat top response
BP, blood pressure; HR, heart rate; VR, valsalva ratio; HRDB, heart rate to deep breathing; SI, sympathetic indexes; PRT, pressure recovery time; VM, valsalva maneuver. Normative data from controls: maximum fall in SBP during head up tilt test b 23.7 mmHg, maximum fall in DBP during head up tilt test b 12 mmHg, maximum HR increase during head up tilt test b 27.1, SI1 b 19.9, SI2 N 3.4, SI3 N −4.2, −2.7 b SI4 b 46.2, PRT (SI5) b 3.1, E:I ratio N 1.4, HRDB N 5.1, 1.2 b Valsalva ratio b 2.2, HR during recovery phase of VM N 77% of baseline HR.
sympathetic hyperactivity) and normal controls was summarized in Table 2. Four patients (patients 1–4) had abnormal decrease in BP response within 3 minutes, which persisted during the entire period of HUT test in 3 patients (patients 2, 3, and 4), and abnormal decrease in BP response was transient in 1 patient (patient 1) for 5 minutes (range of BP decrease; 27–34 mmHg). During the VM, two patients (patients 3 and 4) with abnormal decrease in BP response during HUT test also demonstrated abnormal SI3 and/or SI2 compared to controls. Patient 5 only showed reduced SI3 and PRT (SI5) compared to controls.
Representative cases with persistent abnormal BP decrease during the HUT test in patient 3 and abnormal SIs in patient 5 are shown in Fig. 2A and C, respectively. Six patients (patients 6–11) exhibited significantly elevated HR during the HUT test compared to controls. Two patients (patients 10 and 12) showed exaggerated SI4 compared to controls. Patients with abnormal increase in HR during the HUT test or exaggerated SI4 during the VM (patients 7, 8, 11, and 12) also demonstrated increased VR compared to controls. Illustrative patient cases with abnormal increase in HR response during the HUT test in patient 7 and abnormal VR results in patient 12 are shown in Fig. 3A and B, respectively. Patient
Table 2 Autonomic parameters in patients with sympathetic dysregulation and normal controls. Sympathetic failure
Head up tilt test SBP, baseline, mmHg Maximum fall in SBP, mmHg Mean fall in SBP, mmHg MBP, baseline, mmHg Maximum fall in MBP, mmHg Mean fall in MBP, mmHg DBP, baseline, mmHg Maximum fall in DBP, mmHg Mean fall in DBP, mmHg HR, baseline Maximum increase in HR Mean increase in HR Valsalva maneuver MBP, baseline, mmHg MBP of phase 2E end, mmHg MBP of phase 2 L end, mmHg MBP of phase 4, mmHg SI1 SI2 SI3 SI4 PRT (SI5), sec Cardiovagal test E:I ratio HRDB Valsalva ratio
Sympathetic hyperactivity
Controls
Mean
SD
Mean
SD
Mean
SD
124.8 −26.6a −12.4a 90.6 −18.4a −5.4 69.6 −13.8a −1.6a 56.0 18.6 12.6
17.6 10.2 14.4 13.4 6.0 8.5 10.1 6.8 4.8 4.1 7.7 6.1
112.0 −12.0 −3.1 84.0 −8.3 0.6 64.1 −3.6 3.6 65.0 26.9a 19.7a
14.1 4.9 8.1 9.6 4.2 6.4 6.9 3.7 4.8 8.9 4.1 3.8
117.4 −12.5 −0.6 86.0 −7.3 1.5 64.8 −3.2 3.3 68.7 15.8 11.0
15.2 5.6 6.5 10.5 4.6 4.0 7.6 4.4 3.8 7.8 5.7 5.4
98.0 87.7 90.7 110.7 10.3 3.0a −7.3a 12.7 2.3
16.5 19.4 25.7 22.0 10.1 8.2 11.2 9.7 1.5
90.3 80.6 104.1 120.1 9.7 23.6 13.9 29.9 1.1
11.2 10.7 15.7 25.4 10.9 13.9 8.0 17.2 0.4
87.5 78.0 98.5 109.3 8.6 21.0 11.0 21.7 1.7
9.9 10.9 14.4 17.4 5.7 8.8 7.6 12.2 0.7
1.2 10.1 1.6
0.1 4.0 0.1
0.1 5.3 0.3
1.2 15.0 1.7
0.1 4.9 0.2
1.2 12.0 2.1a
SBP, systolic blood pressure; MBP, mean blood pressure; DBP, diastolic blood pressure; HR, heart rate; E, early; L, late; SI, sympathetic index; PRT, pressure recovery time; HRDB, HR change to deep breathing. a Significant difference as compared to other groups.
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Fig. 2. (A) The head up tilt test in patients with a sympathetic failure. There was a decrease of systolic blood pressure of up to 30 mmHg within 3 minutes after the head up tilt test that is persisted during the entire period of head up tilt test, consistent with classic orthostatic hypotension (patient 3). (B) Valsalva maneuver in healthy subject. Late phase 2 is over the resting MBP level and PRT (SI5) is very short less than 4 seconds. (C) Valsalva maneuver in patient 5 with a sympathetic failure. Late phase 2 is far less than the resting MBP level, and PRT (SI5) is prolonged about 10 seconds. BP, blood pressure; SBP, systolic blood pressure; MBP, mean blood pressure; DBP, diastolic blood pressure; PRT, pressure recovery time; IIE, early phase II; IIL, late phase II.
13 only presented with increased VR. There was no hypervagal response after the HUT test; however, one patient (patient 9) presented with abnormal decrease in HR response after the VM (i.e., hypervagal response). One patient (patient 14) exhibited a decreased cardiovagal response with lower E:I ratio and HRDB. Two patients (patients 1 and 18) showed “flattop” responses in the VM. Three patients (patients 15–17) had normal responses to all of the autonomic function tests (Table 1). 4. Discussion The key finding of our study was that the frequency of autonomic dysfunction was very high in patients with chronic persistent dizziness after excluding of other causes with extensive investigations. In this study, approximately 80% of the patients with chronic persistent dizziness of an unknown origin exhibited at least one autonomic abnormality. Another important finding was that two opposing mechanisms of autonomic dysfunction were related with chronic persistent dizziness: sympathetic failure, which included abnormal decrease in BP response during the HUT test or abnormal SIs in the VM; and sympathetic hyperactivity, which included an abnormal increase in HR response during the HUT test or exaggerated SI4 in the VM. There have been some previous studies [9,10] about autonomic dysfunction in patients with chronic dizziness. In the report [9] using the HUT test, various patterns of autonomic dysfunction were reported, such as neutrally mediated syncope, postural tachycardia syndrome (POTS), and a mildly abnormal heart rate elevation with diastolic hypotension in patients with chronic dizziness. One third (6/18) of our patients also showed abnormal HR increase (compared to controls) during the HUT test, and HR response during the tilting in three patients was compatible with POTS. The POTS is characterized by a sustained HR increase of 30 beats per minute within 10 minutes of the HUT test [11]. Indeed, POTS is a representative syndrome related to orthostatic intolerance [12]. However, it has also been proposed that POTS may contribute to non-orthostatic symptoms, which are not triggered by orthostatic stress, such as gastrointestinal discomfort, urinary symptoms, sleep disturbances, pain, fatigue, or chronic persistent dizziness [11,13]. But,
there was no prior report emphasizing the clinical relevance of POTS as a cause of chronic persistent (not orthostatic) dizziness. Apart from abnormal increased HR during the HUT test speaking for a sympathetic hyperactivity, abnormal BP fall (compared to controls) during the HUT test and SI abnormalities during the VM are also suggested as a cause of chronic persistent dizziness in our study. Abnormal BP decrease during the HUT test of our patients were compatible with orthostatic hypotension (OH), which was defined as a decrease in SBP of at least 20 mmHg or a decrease in DBP of at least 10 mmHg [14]. A number of patients with OH who exhibit none of the typical severe symptoms such as blackouts or near-fainting spells are usually categorized as asymptomatic [15]. However, most patients with asymptomatic OH actually may have subtle symptoms, which are profoundly exacerbated by routine physical activities such as eating, showering, and low-intensity exercise [15]. Our patients performed not only the HUT test but the VM, which was essential for the evaluation of adrenergic autonomic dysfunction [16]. Seventeen percent (3/18) of patients showed reduced SI2 and/or SI3 in VM. Both SI2 and SI3 are calculated based on the BP recovery from the BP fall of the early phase of phase II. The baroreflex arrests the BP fall during the VM and forms the late phase II by an increase in both efferent sympathetic discharge to muscle and plasma norepinephrine concentration [7]. Reduced SI2 and/or SI3 reflecting the failure of vasoconstrictor response are probably the most sensitive trackers of total peripheral adrenergic activation [17]. PRT (SI5) is calculated from the recovery time from BP fall after phase III and is also a valuable index of adrenergic failure [8]. In contrast, exaggerated SI4 which is observed in two patients, manifests increased β-adrenergic tone, which may lead to increased HR response as in patients with POTS. It is very interesting that two opposite abnormalities, sympathetic failure and hyperactivity, can be related with chronic dizziness. We speculated that the disruption in the balance in the sympathetic adrenergic system directed to either overactivity or hypofunction can induce cerebral hypoperfusion, which ultimately causes dizziness symptoms.
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Fig. 3. Blood pressure and heart rate response during the head up tilt test and Valsalva maneuver in patients with a sympathetic hyperactivity. (A) Increased heart rate over 30 beats within 10 minutes without any change of blood pressure during the head up tilt test in patient 7 is consistent with POTS. (B) Exaggerated increase of MBP in phase IV and increased Valsalva ratio during Valsalva maneuver in patient 12. POTS, postural orthostatic tachycardia syndrome; BP, blood pressure; HR, heart rate; SBP, systolic blood pressure; MBP, mean blood pressure; DBP, diastolic blood pressure.
Patient 9 exhibited increased HR during the HUT test and a hypervagal response during the recovery phase of the VM. Sympathetic hyperactivity and hypervagal response (i.e., mixed response) have been previously reported in patients with dizziness of nonvestibular origin [15]. Because higher VR compared to controls was mostly identified in patients with increased HR in the HUT test, we proposed that a higher VR itself might also be considered as a marker of sympathetic hyperactivity. In our study, approximately 2.8% of patients with dizziness who were referred to our dizziness clinic during the 12-month study period had chronic persistent dizziness due to autonomic dysfunction. This was higher than the prevalence (0. 4–1.5%) of purely autonomic dizziness described in previous reports [9,10]. Discordance between our study and previous reports [9,10] could be partly explained in methodological differences. First, we used continuous BP monitoring to detect beat-to-beat BP recording, whereas a previous study [9] used BP monitoring with measurements of one-minute intervals that could not detect brief episodes of transient OH or increased HR response. Second, previous reports [9,10] did not include the VM, which is an essential tool for the evaluation of adrenergic sympathetic dysfunction. The abnormal SIs from the VM can reflect the mild to moderate
adrenergic failure [8]. A higher sensitivity in the screening procedure using beat-to-beat BP recordings and the VM enables the detection of mild autonomic dysfunction and in turn, improves the potential for detecting autonomic dysfunction. The major limitation of our study was the small sample size. The strict exclusion in our study was necessary for excluding other causes of subjective dizziness, but it also diminished the sample size and limited the participation of aged people who tended to have various other disorders. Thus, future studies should be performed with a large sample size. In conclusion, autonomic dysfunction is frequently observed in patients with chronic persistent dizziness of an unknown cause. Dysautonomia with sympathetic failure or hyperactivity might contribute to chronic persistent dizziness. Thus, clinicians should be aware of the possibility of autonomic dysfunction in patients with chronic dizziness, even if the dizziness is not orthostatic but persistent. References [1] Bronstein AM, Lempert T, Seemungal BM. Chronic dizziness: a practical approach. Pract Neurol 2010;10:129–39. [2] Bannister R, Mathias CJ. Autonomic failure: a textbook of clinical disorders of the autonomic nervous system. 4th ed. Oxford; New York: Oxford University Press; 1999.
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[3] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, DSM-IV. 4th ed. Washington, DC: American Psychiatric Association; 1994. [4] Derogatis LR, Unger R. Symptom Checklist-90-Revised. The Corsini Encyclopedia of Psychology. John Wiley & Sons, Inc.; 2010 [5] Derogatis LR, Cleary PA. Factorial invariance across gender for the primary symptom dimensions of the SCL-90. Br J Soc Clin Psychol 1977;16:347–56. [6] Low PA, Tomalia VA, Park KJ. Autonomic function tests: some clinical applications. J Clin Neurol 2013;9:1–8. [7] Vogel ER, Sandroni P, Low PA. Blood pressure recovery from Valsalva maneuver in patients with autonomic failure. Neurology 2005;65:1533–7. [8] Novak P. Assessment of sympathetic index from the Valsalva maneuver. Neurology 2011;76:2010–6. [9] Staab JP, Ruckenstein MJ. Autonomic nervous system function in chronic dizziness. Otol Neurotol 2007;28:854–9. [10] Staab JP, Ruckenstein MJ. Expanding the differential diagnosis of chronic dizziness. Arch Otolaryngol Head Neck Surg 2007;133:170–6.
[11] Low PA, Sandroni P, Joyner M, Shen WK. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol 2009;20:352–8. [12] Thieben MJ, Sandroni P, Sletten DM, Benrud-Larson LM, Fealey RD, Vernino S, et al. Postural orthostatic tachycardia syndrome: the Mayo clinic experience. Mayo Clin Proc 2007;82:308–13. [13] Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc 2012;87:1214–25. [14] Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011;21:69–72. [15] Low PA, Benarroch EE. Clinical autonomic disorders. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2008. [16] 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. [17] Sandroni P, Benarroch EE, Low PA. Pharmacological dissection of components of the Valsalva maneuver in adrenergic failure. J Appl Physiol 1991;71:1563–7.
