Lower wake resting sympathetic and cardiovascular activities in narcolepsy with cataplexy Vincenzo Donadio, MD, PhD Rocco Liguori, MD Stefano Vandi, BSc Fabio Pizza, MD, PhD Yves Dauvilliers, MD, PhD Valentina Leta, MD Maria Pia Giannoccaro, MD Agostino Baruzzi, MD Giuseppe Plazzi, MD
Correspondence to Dr. Donadio: [email protected]
ABSTRACT
Objective: Conflicting data have been reported on resting autonomic tone in narcolepsy with cataplexy (NC), including reduced or increased sympathetic activity; to settle this important point, we aimed to measure the resting sympathetic and cardiovascular activities in patients with NC by direct microneurographic monitoring of muscle sympathetic nerve activity (MSNA) during wakefulness.
Methods: We studied 19 untreated patients with established criteria for NC and hypocretin deficiency and 19 sex- and age-matched healthy subjects. Subjects underwent resting microneurographic recording of MSNA from peroneal nerve and heart rate (HR), whereas blood pressure (BP) was measured with a sphygmomanometer after the end of microneurographic recording. The awake state was continuously monitored by an ambulatory polygraphic recorder. Results: Patients with NC displayed lower resting MSNA, HR, and BP values than controls. Pearson regression analysis showed a correlation between CSF hypocretin-1 level and MSNA or HR, whereas no correlation was found with BP; however, patients with virtually absent hypocretin-1 displayed lower BP than patients with the highest hypocretin-1 value. Conclusions: (1) Patients with NC displayed decreased resting MSNA, HR, and BP during wakefulness, lowering their cardiovascular risk profile; (2) CSF hypocretin-1 deficiency was correlated with MSNA or HR, supporting a direct effect of hypocretin on autonomic regulation; (3) although hypocretin-1 was not correlated with BP, patients with absent hypocretin-1 had lower BP. Neurology® 2014;83:1080–1086 GLOSSARY BMI 5 body mass index; BP 5 blood pressure; HR 5 heart rate; MSNA 5 muscle sympathetic nerve activity; NC 5 narcolepsy with cataplexy.
Narcolepsy with cataplexy (NC) is a chronic sleep disorder thought to be induced by a loss of hypocretin (orexin) in the posterior hypothalamus.1 Several animal studies reported a direct effect of hypocretin on sympathetic and cardiovascular activities during wake,2–4 supporting autonomic involvement in NC. Accordingly, autonomic dysfunctions such as pupillary abnormalities, erectile dysfunction, low body temperature, and cardiovascular abnormalities were often reported in narcoleptic patients.5,6 However, conflicting data have been reported on resting autonomic tone during wake in patients with NC: some studies found a reduced sympathetic tone,7 while others reported increased sympathetic activity.8 This aspect is particularly relevant since increased sympathetic activity represents an unfavorable factor9,10 that may increase the risk of cardiovascular disorders for patients with NC who already present other cardiovascular risk factors such as obesity, diabetes, sleep apnea, and metabolic syndrome.11,12 The contrasting findings on resting sympathetic tone are probably related to the lack of a direct measure of sympathetic activity such as that provided by microneurography. The aim of the present study was to report a direct recording of muscle sympathetic nerve activity (MSNA) by microneurography during wakefulness to establish resting sympathetic and cardiovascular activities in patients with NC.
From IRCCS Istituto delle Scienze Neurologiche (V.D., R.L., S.V., F.P., V.L., M.P.G., A.B., G.P.), Bologna; Dipartimento di Scienze Biomediche e Neuromotorie (R.L., S.V., F.P., M.P.G., G.P.), Università di Bologna, Italy; and Centre de Référence National sur les Maladies Rares (Y.D.), Service de Neurologie, Unité des Troubles du Sommeil, Hôpital Gui-de-Chauliac, INSERM U1061, Montpellier, France. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 1080
© 2014 American Academy of Neurology
METHODS We studied 19 drug-naive patients with NC. The diagnosis was confirmed by polysomnography followed by the Multiple Sleep Latency Test and low or undetectable CSF hypocretin-1 levels (American Academy of Sleep Medicine, 2005)13 (table 1). Patients did not have diabetes or sleep apnea. CSF was collected using standard procedures. Hypocretin-1 assay was performed with a commercially available kit (Human orexin-A RIA Kit, Phoenix Pharmaceutical, Belmont, CA). Nineteen sex- and age-matched healthy subjects without signs of neurologic dysfunction served as controls (table 1). Microneurographic recording was usually performed between 10:00 and 15:00, 3 hours after a light meal. Tobacco, caffeine, and alcohol were not allowed for 12 hours before the examination.
Standard protocol approvals, registrations, and patient consents. The procedures used were approved by the local Human Ethics Committee and followed the Helsinki Declaration regarding international clinical research involving human beings. All subjects gave their written informed consent to the study.
Microneurography. The recording was made with subjects lying down and relaxed. Multiunit postganglionic MSNA from peroneal nerve (posterior to the fibular head) were recorded using a tungsten microelectrode with a tip diameter of a few microns. A reference
Table 1
electrode with low impedance was placed 4–5 cm away. The nerve signal showed the usual amplification (350,000) and filtration (bandpass 700–2,000 Hz) and was further fed through a discriminator for noise reduction and audio monitoring. The original nerve signal was then passed through a resistance-capacitance circuit (time constant 0.1 seconds) to obtain an integrated MSNA burst. An MSNA recording was considered acceptable when it revealed spontaneous, pulsesynchronous bursts fulfilling previously described criteria.14–16 During recording, we also monitored respiratory movements using a thoracic strain gauge and arterial finger blood pressure (BP) continuously monitored by the volume-clamp method (Finometer model, Arnhem, the Netherlands) placing the cuff around the middle phalanx of the third finger on the left hand. Continuous BP monitoring during microneurography is needed to better classify the recorded spontaneous bursts: an inverse correlation between BP and spontaneous bursts is a key criterion to classify the recorded activity as MSNA.14 All recorded signals were subsequently sampled (200 Hz) and stored on a personal computer using locally produced data acquisition software. No special arousing maneuvers were needed during microneurography: this procedure includes electrical stimulation to find the correct nerve placement; then, small needle adjustments are needed to record MSNA, which often evokes a disturbing
Demographic and clinical data MSLT
Patient
Age, y
Sex
Disease duration, y
Hypocretin level, pg/mLa
BMI
mSL
SOREMP, n
99
3
1
30
F
10
28.3
30.8
29 0
2
57
F
16
28.8
0
29 4899
4
99
2
99
3
38
M
5
28.1
14.34
49 42
4
26
F
3
21.1
75
29 54
2
5
50
F
8
26.4
18.4
29 3699
5
6
24
M
5
23.6
37
19 4299
4
99
3
7
26
M
10
26
57.28
59 4
8
32
F
6
19.5
23.57
09 5499
9
20
F
6
20.3
11.24
19 099
4 5 99
10
33
M
18
25
91.96
139 42
2
11
19
F
4
17.9
1.3
39 3099
5
12
38
F
23
21.6
49.83
79 2499
1
13
45
M
10
27.6
17.5
39 3
99
4 99
14
38
M
2
31.4
0
19 36
5
15
25
M
0.5
28.3
0
09 4899
3
99
16
23
M
10
31
12.54
19 12
1
17
32
F
13
19.5
0
29 099
3
18
36
F
6
28.4
76.7
99 4899
3
23.4
99
19 53
5
29 6 28
461
361
—
—
—
19 Mean 6 SD
23
M
2
26.9
32 6 10
10:09
866
25 6 4
37 6 13
10:09
—
23 6 3
b,c
Controls Mean 6 SD
Abbreviations: BMI 5 body mass index; mSL 5 mean sleep latency; MSLT 5 Multiple Sleep Latency Test; SOREMP 5 sleeponset REM periods. a Normal value #110 pg/mL. b p , 0.05 (patients vs controls). c Significant difference. Neurology 83
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1081
cramp sensation. The following resting phase of recording was rather short (15 minutes), and the laboratory was well-lit throughout the recording. Moreover, the awake state was continuously monitored during microneurographic recording in patients with NC, considering their propensity to fall asleep, by an ambulatory polygraphic recorder (Albert Grass Heritage, Colleague TM PSG Model PSG16P-1, Astro-Med, West Warwick, RI) monitoring the following parameters: EEG (C3-A2; C4-A1; O2-A1), right and left electro-oculogram, and superficial EMG of mylohyoideus muscle and left and right anterior tibialis muscles.
Data analysis. Sympathetic bursts occurring during the last 5 minutes of a 15-minute rest were identified by inspection of the mean voltage neurogram, and the amount of activity was expressed as burst incidence (bursts per 100 heartbeats). Resting BP and heart rate (HR) were calculated during the last 5 minutes of microneurographic recording. BP was also measured by sphygmomanometer on the upper arm, supplying a more reliable absolute value than the indirect volume-clamp method. To avoid interference during MSNA recording, sphygmomanometer BP was measured as soon as the recording finished (after 20–40 minutes of supine rest). The mean of 3 measurements (at 5-minute intervals) was usually reported in each subject. Statistics. All values are expressed as mean 6 SD. A normal distribution of analyzed data was verified by Kolmogorov-Smirnov Table 2
Patient
Laboratory findings MSNA, bursts/100 heartbeats
HR, beats/min
SBP, mm Hg
DBP, mm Hg
1
65
63
133
66
2
35
64
132
73
3
33
60
122
73
4
53
79
115
69
5
23
51
108
74
6
27
56
118
59
7
40
58
112
57
8
22
61
101
62
9
31
77
114
64
10
62
74
95
60
11
28
67
104
66
12
34
68
109
64
13
41
55
112
73
14
32
52
108
66
15
22
50
97
47
16
38
60
100
60
17
43
55
94
58
18
33
72
130
80
19
21
120
73
Mean 6 SD
63 a,c
b,c
36 6 13
62 6 9
112 6 12
65 6 8b,c
49 6 13
71 6 11
120 6 15
73 6 9
Controls Mean 6 SD
Abbreviations: DBP 5 diastolic blood pressure; HR 5 heart rate; MSNA 5 muscle sympathetic nerve activity; SBP 5 systolic blood pressure. a p , 0.01. b p , 0.05 (patients vs controls). c Significant difference. 1082
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test. Statistical analysis was then performed by 2-tailed Student t test for unpaired data to compare resting data in patients with NC and controls; Pearson linear regression analysis was used to demonstrate possible correlation between analyzed parameters; p , 0.05 was considered significant. RESULTS Patients with NC showed MSNA with normal cardiac rhythm but burst incidence was lower than in controls (table 2; figure 1). Resting HR was also lower in patients with NC with respect to controls (table 2). Similarly, sphygmomanometer measurement made after the recording disclosed a lower value for diastolic BP in patients with NC compared to controls, whereas the difference was close to the statistical level (p 5 0.073) for systolic BP (table 2). The same result was found analyzing BP during microneurography by means of the volume-clamp method: diastolic BP was lower in patients with NC with respect to controls (63 6 15 and 76 6 13 mm Hg, respectively; p , 0.01), but statistical significance was not reached for systolic BP (125 6 15 and 133 6 22; p 5 0.23). As expected, patients with NC displayed a slightly higher body mass index (BMI) than controls (table 1). Pearson regression analysis showed a correlation between CSF hypocretin-1 level and MSNA (r 5 0.5; p , 0.05; figure 2A) or HR (r 5 0.6; p , 0.01; figure 2B), whereas no correlation was found with BP or BMI. BP, BMI, or disease duration were not correlated with any parameters. However, patients with virtually absent hypocretin-1 (5 patients: ranging from 0 to 1.3 pg/mL) displayed a lower mean systolic BP and diastolic BP than patients with the highest hypocretin-1 levels (5 patients: ranging from 57.3 to 92 pg/mL): 107 6 15 and 62 6 10 mm Hg vs 112 6 13 and 66 6 9 mm Hg, respectively; by contrast, BMI showed a similar value in both groups (25 6 6 and 25 6 3). DISCUSSION This study evaluated resting sympathetic and cardiovascular activities in untreated patients with NC. The following main results were obtained: (1) patients with NC displayed decreased resting MSNA, HR, and BP during wakefulness, lowering their cardiovascular risk profile; (2) CSF hypocretin-1 deficiency was correlated with MSNA or HR, supporting a direct effect of hypocretin on autonomic regulation; (3) although hypocretin-1 was not correlated with BP, patients with undetectable CSF hypocretin-1 had lower BP. Although the hypocretin-containing cell bodies are mainly restricted to the lateral and dorsomedial hypothalamus area, hypocretin-containing nerve terminals and receptors are widely distributed throughout the CNS, including areas (i.e., brainstem structures) known to play a central role in autonomic and cardiovascular regulation.17 Specifically, several lines of evidence in animal models suggest a direct
Figure 1
Resting muscle sympathetic nerve activity and cardiovascular activity in 2 patients with narcolepsy and matched healthy controls
Muscle sympathetic nerve activity (MSNA) microneurographic recording from 2 patients with narcolepsy with cataplexy (NC) and absent (A.a) or low (A.b) CSF hypocretin and 2 matched healthy controls (B.a and B.b), together with heart rate (HR) monitoring. Blood pressure (BP) was measured with a sphygmomanometer after the end of microneurographic recording. (A.a and B.a) The patient with NC (patient 15 in the tables) displayed lower MSNA, HR, and BP than the healthy control. (A.b and B.b) In this different example, the patient with NC (patient 18 in the tables), although showing similar HR and BP as the healthy control, displayed lower MSNA, pinpointing the conclusion that resting sympathetic tone difference between the patient and the control was not influenced by HR.
effect of the hypocretin system on cardiac and extracardiac sympathetic preganglionic neurons, supporting a direct and wide regulation of sympathetic activity.4 Accordingly, functional studies have shown that hypocretins evoke increased cardiovascular and sympathetic activities when administrated intracerebroventricularly2,3 or intrathecally4 in awake rats. An important characteristic of hypocretin neurons is a state-dependent activity
Figure 2
since they are specifically active during active wake but silent or occasionally active during quiet wake, nonREM, and REM (except during its phasic discharge) sleep in animals.18 A logical corollary of these findings is that hypocretin deficiency should lower sympathetic and cardiovascular activities during wake. Animal studies fit this conclusion since lower HR, BP, and sympathetic activities during wakefulness were reported in both
Pearson correlation between hypocretin and muscle sympathetic nerve activity or heart rate
CSF hypocretin (HCRT) value (pg/mL; y axis) showed a significant correlation with muscle sympathetic nerve activity (MSNA) (bursts/100 heartbeats [HB]; x axis: r 5 0.5; p , 0.05) (A) or heart rate (HR) (beats/min; x axis: r 5 0.6; p , 0.01) (B). These data support a direct effect of hypocretin deficiency on MSNA or HR regulation. Neurology 83
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hypocretin-deficient knockout mice19,20 and hypocretin neuron–ablated transgenic mice.21,22 By contrast, human studies suggested a sympathetic activation during wake in patients with NC, conflicting with experimental models.8,23 However, these studies were based on indirect tests of autonomic cardiac activity (i.e., heart rate variability), which is influenced by parasympathetic as well as sympathetic systems, both innervated by hypocretin neurons.24 Consequently, this approach may not differentiate the selective effect of hypocretin deficiency on sympathetic or parasympathetic outflow. Accordingly, sympathovagal balance during wakefulness was reportedly decreased23 but also normal25 or increased7 in patients with NC. We recorded autonomic activity by microneurography, which is a direct intraneural technique selectively quantifying peripheral sympathetic outflow. Our data demonstrated lower resting sympathetic tone in patients with NC compared to a matched healthy control group, in agreement with animal data4,21,26 and as expected from the hypocretin deficiency. We also found a resting wake HR decrease in patients with NC, as previously reported,27 which could be mainly the expression of a generalized decrease of sympathetic outflow since in resting awake state MSNA was coupled with cardiac sympathetic activity.28 CSF hypocretin-1 deficiency was correlated with MSNA or HR, supporting a direct effect of hypocretin on autonomic regulation. This implies that hypocretin-1–deficient patients with NC with the higher hypocretin-1 values (although below the normal cutoff value of 110 pg/mL) may display wake MSNA (i.e., patients 1, 4, and 10 of table 2) or HR (i.e., patients 4, 9, 10, and 18) values comparable to those of controls, possibly explaining previously conflicting findings on resting wake sympathetic tone. Our data demonstrated a decrease of resting BP values in patients with NC. Although hypocretin-1 deficiency was not correlated with resting BP, patients with undetectable CSF hypocretin-1 had lower BP than the patients with the highest CSF hypocretin-1 level. This finding agrees with animal data showing that orexin administration may raise BP in a dosedependent manner.3,29,30 However, taken together, our data suggest that hypocretin deficiency may influence resting BP awake level, likely by means of decreased sympathetic outflow. The lack of correlation between hypocretin-1 level or sympathetic activity and BP could be explained by considering that resting awake BP is influenced by several additional mechanisms, including baroreflex activity, hormonal factors, renal activity, and cardiac output, acting together with MSNA.31 It is unlikely that the lack of correlation between MSNA and BP could be due to the absence of measurement synchronism since MSNA usually shows a stable and reproducible value over time.28 Resting lower awake BP was previously reported in patients with NC.7,32 Other studies8,33 did not confirm 1084
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this finding but were limited by small cohorts or the lack of a prolonged resting period before BP measurement. The decrease in resting sympathetic and cardiovascular activities displayed by patients with NC was likely induced by an abnormal regulatory mechanism, as in specific situations (i.e., cataplectic attack) MSNA and BP may increase in patients with NC.34 These data suggest that autonomic central areas respond well and are likely preserved in NC, in agreement with the hypocretin pathogenesis of this disorder. A limitation of this study is the different BMI between patients and controls, as obesity may influence MSNA.35 Nevertheless, the following aspects should exclude a significant influence of higher body weight on decreased resting wake sympathetic tone in NC: (1) obesity should increase MSNA,35,36 which in turn abolishes rather than accentuates the resting sympathetic tone difference between patients with NC and controls; (2) obese patients without hypertension such as patients with NC might not show an MSNA increase37; (3) the effect of obesity on MSNA is probably complex, as is it influenced by age36 and sex,38 which were both matched to controls in our patients with NC (table 1). However, future studies need to explore the possible involvement of sympathetic activity in obesity-associated NC considering the prominent effect of sympathetic activity on lipolysis.37 An important implication of our study is that decreased awake sympathetic tone lowered the cardiovascular risk profile in patients with NC, counteracting different risk factors such as obesity, sleep apnea, diabetes, and the nondipping BP during sleep often displayed by patients with NC.8,12,27 Accordingly, histologic and ultrastructural analysis of cardiovascular and renal tissues did not reveal subclinical hypertensive organ damage in middle-aged hypocretin-deficient narcoleptic mice.39 However, although a recent follow-up study evaluating narcoleptic comorbidities did not show a greater incidence of cardiovascular disorders, it demonstrated a tendency toward higher mortality, although not significant in the narcoleptic population,12 which was also supported by a different study.40 This means that the clinical impact of our result should be carefully evaluated by a longer follow-up study involving a large cohort of patients with NC before drawing any definite conclusions. AUTHOR CONTRIBUTIONS Dr. Donadio: drafting/revising the manuscript, study concept and design, analysis and interpretation of data, study supervision. Dr. Liguori: drafting/revising the manuscript, study concept and design, analysis and interpretation of data. S. Vandi: study concept and design, analysis and interpretation of data. Dr. Pizza: study concept and design, analysis and interpretation of data. Dr. Dauvilliers: drafting/revising the manuscript, analysis and interpretation of data. Dr. Leta: study concept and design, analysis and interpretation of data. Dr. Giannoccaro: study concept and design, analysis and interpretation of data. Dr. Baruzzi: study concept and design, analysis and interpretation of data. Dr. Plazzi: drafting/ revising the manuscript, study concept and design, analysis and interpretation of data, study supervision.
ACKNOWLEDGMENT
15.
The authors thank Anne Collins for English editing and Massimo Armaroli for technical collaboration.
STUDY FUNDING
16.
No targeted funding reported.
DISCLOSURE Dr. Donadio has received support for travel to meetings from CSL Behring. Dr. Liguori, S. Vandi, and Dr. Pizza report no disclosures relevant to the manuscript. Dr. Dauvilliers has received speaker’s honoraria and support for travel to meetings from UCB Pharma, Jazz Pharmaceuticals, and Bioprojet. Dr. Leta reports no disclosures relevant to the manuscript. Dr. Giannoccaro has received support for travel to meetings from Ipsen Pharma. Dr. Baruzzi reports no disclosures relevant to the manuscript. Dr. Plazzi has received consultancies from UCB Pharma, Jazz Pharmaceuticals, and Bioprojet. Go to Neurology.org for full disclosures.
17.
18. 19.
20.
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Lower wake resting sympathetic and cardiovascular activities in narcolepsy with cataplexy Vincenzo Donadio, Rocco Liguori, Stefano Vandi, et al. Neurology 2014;83;1080-1086 Published Online before print August 6, 2014 DOI 10.1212/WNL.0000000000000793 This information is current as of August 6, 2014 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Correspondence to Dr. Donadio: [email protected]
ABSTRACT
Objective: Conflicting data have been reported on resting autonomic tone in narcolepsy with cataplexy (NC), including reduced or increased sympathetic activity; to settle this important point, we aimed to measure the resting sympathetic and cardiovascular activities in patients with NC by direct microneurographic monitoring of muscle sympathetic nerve activity (MSNA) during wakefulness.
Methods: We studied 19 untreated patients with established criteria for NC and hypocretin deficiency and 19 sex- and age-matched healthy subjects. Subjects underwent resting microneurographic recording of MSNA from peroneal nerve and heart rate (HR), whereas blood pressure (BP) was measured with a sphygmomanometer after the end of microneurographic recording. The awake state was continuously monitored by an ambulatory polygraphic recorder. Results: Patients with NC displayed lower resting MSNA, HR, and BP values than controls. Pearson regression analysis showed a correlation between CSF hypocretin-1 level and MSNA or HR, whereas no correlation was found with BP; however, patients with virtually absent hypocretin-1 displayed lower BP than patients with the highest hypocretin-1 value. Conclusions: (1) Patients with NC displayed decreased resting MSNA, HR, and BP during wakefulness, lowering their cardiovascular risk profile; (2) CSF hypocretin-1 deficiency was correlated with MSNA or HR, supporting a direct effect of hypocretin on autonomic regulation; (3) although hypocretin-1 was not correlated with BP, patients with absent hypocretin-1 had lower BP. Neurology® 2014;83:1080–1086 GLOSSARY BMI 5 body mass index; BP 5 blood pressure; HR 5 heart rate; MSNA 5 muscle sympathetic nerve activity; NC 5 narcolepsy with cataplexy.
Narcolepsy with cataplexy (NC) is a chronic sleep disorder thought to be induced by a loss of hypocretin (orexin) in the posterior hypothalamus.1 Several animal studies reported a direct effect of hypocretin on sympathetic and cardiovascular activities during wake,2–4 supporting autonomic involvement in NC. Accordingly, autonomic dysfunctions such as pupillary abnormalities, erectile dysfunction, low body temperature, and cardiovascular abnormalities were often reported in narcoleptic patients.5,6 However, conflicting data have been reported on resting autonomic tone during wake in patients with NC: some studies found a reduced sympathetic tone,7 while others reported increased sympathetic activity.8 This aspect is particularly relevant since increased sympathetic activity represents an unfavorable factor9,10 that may increase the risk of cardiovascular disorders for patients with NC who already present other cardiovascular risk factors such as obesity, diabetes, sleep apnea, and metabolic syndrome.11,12 The contrasting findings on resting sympathetic tone are probably related to the lack of a direct measure of sympathetic activity such as that provided by microneurography. The aim of the present study was to report a direct recording of muscle sympathetic nerve activity (MSNA) by microneurography during wakefulness to establish resting sympathetic and cardiovascular activities in patients with NC.
From IRCCS Istituto delle Scienze Neurologiche (V.D., R.L., S.V., F.P., V.L., M.P.G., A.B., G.P.), Bologna; Dipartimento di Scienze Biomediche e Neuromotorie (R.L., S.V., F.P., M.P.G., G.P.), Università di Bologna, Italy; and Centre de Référence National sur les Maladies Rares (Y.D.), Service de Neurologie, Unité des Troubles du Sommeil, Hôpital Gui-de-Chauliac, INSERM U1061, Montpellier, France. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 1080
© 2014 American Academy of Neurology
METHODS We studied 19 drug-naive patients with NC. The diagnosis was confirmed by polysomnography followed by the Multiple Sleep Latency Test and low or undetectable CSF hypocretin-1 levels (American Academy of Sleep Medicine, 2005)13 (table 1). Patients did not have diabetes or sleep apnea. CSF was collected using standard procedures. Hypocretin-1 assay was performed with a commercially available kit (Human orexin-A RIA Kit, Phoenix Pharmaceutical, Belmont, CA). Nineteen sex- and age-matched healthy subjects without signs of neurologic dysfunction served as controls (table 1). Microneurographic recording was usually performed between 10:00 and 15:00, 3 hours after a light meal. Tobacco, caffeine, and alcohol were not allowed for 12 hours before the examination.
Standard protocol approvals, registrations, and patient consents. The procedures used were approved by the local Human Ethics Committee and followed the Helsinki Declaration regarding international clinical research involving human beings. All subjects gave their written informed consent to the study.
Microneurography. The recording was made with subjects lying down and relaxed. Multiunit postganglionic MSNA from peroneal nerve (posterior to the fibular head) were recorded using a tungsten microelectrode with a tip diameter of a few microns. A reference
Table 1
electrode with low impedance was placed 4–5 cm away. The nerve signal showed the usual amplification (350,000) and filtration (bandpass 700–2,000 Hz) and was further fed through a discriminator for noise reduction and audio monitoring. The original nerve signal was then passed through a resistance-capacitance circuit (time constant 0.1 seconds) to obtain an integrated MSNA burst. An MSNA recording was considered acceptable when it revealed spontaneous, pulsesynchronous bursts fulfilling previously described criteria.14–16 During recording, we also monitored respiratory movements using a thoracic strain gauge and arterial finger blood pressure (BP) continuously monitored by the volume-clamp method (Finometer model, Arnhem, the Netherlands) placing the cuff around the middle phalanx of the third finger on the left hand. Continuous BP monitoring during microneurography is needed to better classify the recorded spontaneous bursts: an inverse correlation between BP and spontaneous bursts is a key criterion to classify the recorded activity as MSNA.14 All recorded signals were subsequently sampled (200 Hz) and stored on a personal computer using locally produced data acquisition software. No special arousing maneuvers were needed during microneurography: this procedure includes electrical stimulation to find the correct nerve placement; then, small needle adjustments are needed to record MSNA, which often evokes a disturbing
Demographic and clinical data MSLT
Patient
Age, y
Sex
Disease duration, y
Hypocretin level, pg/mLa
BMI
mSL
SOREMP, n
99
3
1
30
F
10
28.3
30.8
29 0
2
57
F
16
28.8
0
29 4899
4
99
2
99
3
38
M
5
28.1
14.34
49 42
4
26
F
3
21.1
75
29 54
2
5
50
F
8
26.4
18.4
29 3699
5
6
24
M
5
23.6
37
19 4299
4
99
3
7
26
M
10
26
57.28
59 4
8
32
F
6
19.5
23.57
09 5499
9
20
F
6
20.3
11.24
19 099
4 5 99
10
33
M
18
25
91.96
139 42
2
11
19
F
4
17.9
1.3
39 3099
5
12
38
F
23
21.6
49.83
79 2499
1
13
45
M
10
27.6
17.5
39 3
99
4 99
14
38
M
2
31.4
0
19 36
5
15
25
M
0.5
28.3
0
09 4899
3
99
16
23
M
10
31
12.54
19 12
1
17
32
F
13
19.5
0
29 099
3
18
36
F
6
28.4
76.7
99 4899
3
23.4
99
19 53
5
29 6 28
461
361
—
—
—
19 Mean 6 SD
23
M
2
26.9
32 6 10
10:09
866
25 6 4
37 6 13
10:09
—
23 6 3
b,c
Controls Mean 6 SD
Abbreviations: BMI 5 body mass index; mSL 5 mean sleep latency; MSLT 5 Multiple Sleep Latency Test; SOREMP 5 sleeponset REM periods. a Normal value #110 pg/mL. b p , 0.05 (patients vs controls). c Significant difference. Neurology 83
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1081
cramp sensation. The following resting phase of recording was rather short (15 minutes), and the laboratory was well-lit throughout the recording. Moreover, the awake state was continuously monitored during microneurographic recording in patients with NC, considering their propensity to fall asleep, by an ambulatory polygraphic recorder (Albert Grass Heritage, Colleague TM PSG Model PSG16P-1, Astro-Med, West Warwick, RI) monitoring the following parameters: EEG (C3-A2; C4-A1; O2-A1), right and left electro-oculogram, and superficial EMG of mylohyoideus muscle and left and right anterior tibialis muscles.
Data analysis. Sympathetic bursts occurring during the last 5 minutes of a 15-minute rest were identified by inspection of the mean voltage neurogram, and the amount of activity was expressed as burst incidence (bursts per 100 heartbeats). Resting BP and heart rate (HR) were calculated during the last 5 minutes of microneurographic recording. BP was also measured by sphygmomanometer on the upper arm, supplying a more reliable absolute value than the indirect volume-clamp method. To avoid interference during MSNA recording, sphygmomanometer BP was measured as soon as the recording finished (after 20–40 minutes of supine rest). The mean of 3 measurements (at 5-minute intervals) was usually reported in each subject. Statistics. All values are expressed as mean 6 SD. A normal distribution of analyzed data was verified by Kolmogorov-Smirnov Table 2
Patient
Laboratory findings MSNA, bursts/100 heartbeats
HR, beats/min
SBP, mm Hg
DBP, mm Hg
1
65
63
133
66
2
35
64
132
73
3
33
60
122
73
4
53
79
115
69
5
23
51
108
74
6
27
56
118
59
7
40
58
112
57
8
22
61
101
62
9
31
77
114
64
10
62
74
95
60
11
28
67
104
66
12
34
68
109
64
13
41
55
112
73
14
32
52
108
66
15
22
50
97
47
16
38
60
100
60
17
43
55
94
58
18
33
72
130
80
19
21
120
73
Mean 6 SD
63 a,c
b,c
36 6 13
62 6 9
112 6 12
65 6 8b,c
49 6 13
71 6 11
120 6 15
73 6 9
Controls Mean 6 SD
Abbreviations: DBP 5 diastolic blood pressure; HR 5 heart rate; MSNA 5 muscle sympathetic nerve activity; SBP 5 systolic blood pressure. a p , 0.01. b p , 0.05 (patients vs controls). c Significant difference. 1082
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test. Statistical analysis was then performed by 2-tailed Student t test for unpaired data to compare resting data in patients with NC and controls; Pearson linear regression analysis was used to demonstrate possible correlation between analyzed parameters; p , 0.05 was considered significant. RESULTS Patients with NC showed MSNA with normal cardiac rhythm but burst incidence was lower than in controls (table 2; figure 1). Resting HR was also lower in patients with NC with respect to controls (table 2). Similarly, sphygmomanometer measurement made after the recording disclosed a lower value for diastolic BP in patients with NC compared to controls, whereas the difference was close to the statistical level (p 5 0.073) for systolic BP (table 2). The same result was found analyzing BP during microneurography by means of the volume-clamp method: diastolic BP was lower in patients with NC with respect to controls (63 6 15 and 76 6 13 mm Hg, respectively; p , 0.01), but statistical significance was not reached for systolic BP (125 6 15 and 133 6 22; p 5 0.23). As expected, patients with NC displayed a slightly higher body mass index (BMI) than controls (table 1). Pearson regression analysis showed a correlation between CSF hypocretin-1 level and MSNA (r 5 0.5; p , 0.05; figure 2A) or HR (r 5 0.6; p , 0.01; figure 2B), whereas no correlation was found with BP or BMI. BP, BMI, or disease duration were not correlated with any parameters. However, patients with virtually absent hypocretin-1 (5 patients: ranging from 0 to 1.3 pg/mL) displayed a lower mean systolic BP and diastolic BP than patients with the highest hypocretin-1 levels (5 patients: ranging from 57.3 to 92 pg/mL): 107 6 15 and 62 6 10 mm Hg vs 112 6 13 and 66 6 9 mm Hg, respectively; by contrast, BMI showed a similar value in both groups (25 6 6 and 25 6 3). DISCUSSION This study evaluated resting sympathetic and cardiovascular activities in untreated patients with NC. The following main results were obtained: (1) patients with NC displayed decreased resting MSNA, HR, and BP during wakefulness, lowering their cardiovascular risk profile; (2) CSF hypocretin-1 deficiency was correlated with MSNA or HR, supporting a direct effect of hypocretin on autonomic regulation; (3) although hypocretin-1 was not correlated with BP, patients with undetectable CSF hypocretin-1 had lower BP. Although the hypocretin-containing cell bodies are mainly restricted to the lateral and dorsomedial hypothalamus area, hypocretin-containing nerve terminals and receptors are widely distributed throughout the CNS, including areas (i.e., brainstem structures) known to play a central role in autonomic and cardiovascular regulation.17 Specifically, several lines of evidence in animal models suggest a direct
Figure 1
Resting muscle sympathetic nerve activity and cardiovascular activity in 2 patients with narcolepsy and matched healthy controls
Muscle sympathetic nerve activity (MSNA) microneurographic recording from 2 patients with narcolepsy with cataplexy (NC) and absent (A.a) or low (A.b) CSF hypocretin and 2 matched healthy controls (B.a and B.b), together with heart rate (HR) monitoring. Blood pressure (BP) was measured with a sphygmomanometer after the end of microneurographic recording. (A.a and B.a) The patient with NC (patient 15 in the tables) displayed lower MSNA, HR, and BP than the healthy control. (A.b and B.b) In this different example, the patient with NC (patient 18 in the tables), although showing similar HR and BP as the healthy control, displayed lower MSNA, pinpointing the conclusion that resting sympathetic tone difference between the patient and the control was not influenced by HR.
effect of the hypocretin system on cardiac and extracardiac sympathetic preganglionic neurons, supporting a direct and wide regulation of sympathetic activity.4 Accordingly, functional studies have shown that hypocretins evoke increased cardiovascular and sympathetic activities when administrated intracerebroventricularly2,3 or intrathecally4 in awake rats. An important characteristic of hypocretin neurons is a state-dependent activity
Figure 2
since they are specifically active during active wake but silent or occasionally active during quiet wake, nonREM, and REM (except during its phasic discharge) sleep in animals.18 A logical corollary of these findings is that hypocretin deficiency should lower sympathetic and cardiovascular activities during wake. Animal studies fit this conclusion since lower HR, BP, and sympathetic activities during wakefulness were reported in both
Pearson correlation between hypocretin and muscle sympathetic nerve activity or heart rate
CSF hypocretin (HCRT) value (pg/mL; y axis) showed a significant correlation with muscle sympathetic nerve activity (MSNA) (bursts/100 heartbeats [HB]; x axis: r 5 0.5; p , 0.05) (A) or heart rate (HR) (beats/min; x axis: r 5 0.6; p , 0.01) (B). These data support a direct effect of hypocretin deficiency on MSNA or HR regulation. Neurology 83
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hypocretin-deficient knockout mice19,20 and hypocretin neuron–ablated transgenic mice.21,22 By contrast, human studies suggested a sympathetic activation during wake in patients with NC, conflicting with experimental models.8,23 However, these studies were based on indirect tests of autonomic cardiac activity (i.e., heart rate variability), which is influenced by parasympathetic as well as sympathetic systems, both innervated by hypocretin neurons.24 Consequently, this approach may not differentiate the selective effect of hypocretin deficiency on sympathetic or parasympathetic outflow. Accordingly, sympathovagal balance during wakefulness was reportedly decreased23 but also normal25 or increased7 in patients with NC. We recorded autonomic activity by microneurography, which is a direct intraneural technique selectively quantifying peripheral sympathetic outflow. Our data demonstrated lower resting sympathetic tone in patients with NC compared to a matched healthy control group, in agreement with animal data4,21,26 and as expected from the hypocretin deficiency. We also found a resting wake HR decrease in patients with NC, as previously reported,27 which could be mainly the expression of a generalized decrease of sympathetic outflow since in resting awake state MSNA was coupled with cardiac sympathetic activity.28 CSF hypocretin-1 deficiency was correlated with MSNA or HR, supporting a direct effect of hypocretin on autonomic regulation. This implies that hypocretin-1–deficient patients with NC with the higher hypocretin-1 values (although below the normal cutoff value of 110 pg/mL) may display wake MSNA (i.e., patients 1, 4, and 10 of table 2) or HR (i.e., patients 4, 9, 10, and 18) values comparable to those of controls, possibly explaining previously conflicting findings on resting wake sympathetic tone. Our data demonstrated a decrease of resting BP values in patients with NC. Although hypocretin-1 deficiency was not correlated with resting BP, patients with undetectable CSF hypocretin-1 had lower BP than the patients with the highest CSF hypocretin-1 level. This finding agrees with animal data showing that orexin administration may raise BP in a dosedependent manner.3,29,30 However, taken together, our data suggest that hypocretin deficiency may influence resting BP awake level, likely by means of decreased sympathetic outflow. The lack of correlation between hypocretin-1 level or sympathetic activity and BP could be explained by considering that resting awake BP is influenced by several additional mechanisms, including baroreflex activity, hormonal factors, renal activity, and cardiac output, acting together with MSNA.31 It is unlikely that the lack of correlation between MSNA and BP could be due to the absence of measurement synchronism since MSNA usually shows a stable and reproducible value over time.28 Resting lower awake BP was previously reported in patients with NC.7,32 Other studies8,33 did not confirm 1084
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this finding but were limited by small cohorts or the lack of a prolonged resting period before BP measurement. The decrease in resting sympathetic and cardiovascular activities displayed by patients with NC was likely induced by an abnormal regulatory mechanism, as in specific situations (i.e., cataplectic attack) MSNA and BP may increase in patients with NC.34 These data suggest that autonomic central areas respond well and are likely preserved in NC, in agreement with the hypocretin pathogenesis of this disorder. A limitation of this study is the different BMI between patients and controls, as obesity may influence MSNA.35 Nevertheless, the following aspects should exclude a significant influence of higher body weight on decreased resting wake sympathetic tone in NC: (1) obesity should increase MSNA,35,36 which in turn abolishes rather than accentuates the resting sympathetic tone difference between patients with NC and controls; (2) obese patients without hypertension such as patients with NC might not show an MSNA increase37; (3) the effect of obesity on MSNA is probably complex, as is it influenced by age36 and sex,38 which were both matched to controls in our patients with NC (table 1). However, future studies need to explore the possible involvement of sympathetic activity in obesity-associated NC considering the prominent effect of sympathetic activity on lipolysis.37 An important implication of our study is that decreased awake sympathetic tone lowered the cardiovascular risk profile in patients with NC, counteracting different risk factors such as obesity, sleep apnea, diabetes, and the nondipping BP during sleep often displayed by patients with NC.8,12,27 Accordingly, histologic and ultrastructural analysis of cardiovascular and renal tissues did not reveal subclinical hypertensive organ damage in middle-aged hypocretin-deficient narcoleptic mice.39 However, although a recent follow-up study evaluating narcoleptic comorbidities did not show a greater incidence of cardiovascular disorders, it demonstrated a tendency toward higher mortality, although not significant in the narcoleptic population,12 which was also supported by a different study.40 This means that the clinical impact of our result should be carefully evaluated by a longer follow-up study involving a large cohort of patients with NC before drawing any definite conclusions. AUTHOR CONTRIBUTIONS Dr. Donadio: drafting/revising the manuscript, study concept and design, analysis and interpretation of data, study supervision. Dr. Liguori: drafting/revising the manuscript, study concept and design, analysis and interpretation of data. S. Vandi: study concept and design, analysis and interpretation of data. Dr. Pizza: study concept and design, analysis and interpretation of data. Dr. Dauvilliers: drafting/revising the manuscript, analysis and interpretation of data. Dr. Leta: study concept and design, analysis and interpretation of data. Dr. Giannoccaro: study concept and design, analysis and interpretation of data. Dr. Baruzzi: study concept and design, analysis and interpretation of data. Dr. Plazzi: drafting/ revising the manuscript, study concept and design, analysis and interpretation of data, study supervision.
ACKNOWLEDGMENT
15.
The authors thank Anne Collins for English editing and Massimo Armaroli for technical collaboration.
STUDY FUNDING
16.
No targeted funding reported.
DISCLOSURE Dr. Donadio has received support for travel to meetings from CSL Behring. Dr. Liguori, S. Vandi, and Dr. Pizza report no disclosures relevant to the manuscript. Dr. Dauvilliers has received speaker’s honoraria and support for travel to meetings from UCB Pharma, Jazz Pharmaceuticals, and Bioprojet. Dr. Leta reports no disclosures relevant to the manuscript. Dr. Giannoccaro has received support for travel to meetings from Ipsen Pharma. Dr. Baruzzi reports no disclosures relevant to the manuscript. Dr. Plazzi has received consultancies from UCB Pharma, Jazz Pharmaceuticals, and Bioprojet. Go to Neurology.org for full disclosures.
17.
18. 19.
20.
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Neurology 83
September 16, 2014
Lower wake resting sympathetic and cardiovascular activities in narcolepsy with cataplexy Vincenzo Donadio, Rocco Liguori, Stefano Vandi, et al. Neurology 2014;83;1080-1086 Published Online before print August 6, 2014 DOI 10.1212/WNL.0000000000000793 This information is current as of August 6, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/12/1080.full.html
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This article cites 39 articles, 8 of which you can access for free at: http://www.neurology.org/content/83/12/1080.full.html##ref-list-1
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