Agrypnia Excitata: A microneurographic study of muscle sympathetic nerve activity

Clinical Neurophysiology 120 (2009) 1139–1142

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Agrypnia Excitata: A microneurographic study of muscle sympathetic nerve activity V. Donadio a,*, P. Montagna a, M. Pennisi b, R. Rinaldi c, V. Di Stasi a, P. Avoni a, E. Bugiardini a, M.P. Giannoccaro a, P. Cortelli a, G. Plazzi a, A. Baruzzi a, R. Liguori a a

Department of Neurological Sciences, University of Bologna, Via U. Foscolo 7, 40123 Bologna, Italy Department of Neurological Sciences, University of Catania, Italy c Unit of Neurology, S. Orsola-Malpighi Hospital, University of Bologna, Via Albertoni 15, 40138 Bologna, Italy b

a r t i c l e

i n f o

Article history: Accepted 11 April 2009 Available online 12 May 2009 Keywords: Agrypnia Excitata Muscle sympathetic nerve activity Insomnia Microneurography

a b s t r a c t Objective: Agrypnia Excitata (AE) is characterized by autonomic over-activity and cardiovascular fluctuations but direct evidence of sympathoexcitation is lacking. AE is a common feature of acquired (i.e. Morvan’s syndrome – MS) and genetic (i.e. fatal familial insomnia – FFI) conditions where a dysfunction of the thalamo-limbic system has been suggested. The aim of this study is to report the first microneurographic recordings of sympathetic activity in acquired and genetic AE to investigate the pattern of sympathetic activation. Methods: We describe two patients presenting acquired AE (MS) as demonstrated by elevated serum antibody levels to voltage-gated potassium channels and one patient with genetically confirmed FFI. Patients and fifteen sex and age-matched healthy controls underwent microneurography from peroneal nerve to assess muscle sympathetic nerve activity (MSNA) and heart rate (HR). Results: Mean level of resting awake MSNA and HR was significantly increased in patients compared to controls. Patients presented a similar pattern of MSNA with a normal cardiac rhythmicity and a very high burst incidence expressed in approximately each cardiac beat. Conclusions: Acquired and genetic AE presented a resting awake sympathetic over-activity. Significance: AE patients may develop high blood pressure and/or cardiovascular instability potentially increasing the morbility/mortality of the underlying disorders. Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Agrypnia Excitata (AE) has been proposed as a neurological syndrome characterized by severe insomnia, loss of slow-wave sleep, enacted dreams and motor and autonomic over-activity. It is a feature common to clinical conditions such as Delirium Tremens (DT) (Plazzi et al., 1999), Morvan’s syndrome (MS) (Liguori et al., 2001), fatal familial insomnia (FFI) (Lugaresi et al., 1986), Mulvihill–Smith syndrome (MSS) (Ferri et al., 2005) and sporadic Creutzfeldt–Jacob (SCJ) disease (La Morgia et al., 2009). A common pathogenesis involving a dysfunction of the thalamo-limbic system has been implicated in the cause of AE (Lugaresi and Provini, 2001; Montagna and Lugaresi, 2002). The term Excitata was used to describe the marked motor and autonomic hyperactivity involving mainly the sympathetic system leading to insomnia (Agrypnia) and cardiovascular fluctuations which may increase the morbility/mortality of the underlying disorders (Elam, 2003).

* Corresponding author. Address: Dipartimento di Scienze Neurologiche, Università di Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy. Tel.: +39 051 2092950; fax: +39 051 2092915. E-mail address: [email protected] (V. Donadio).

The sympathetic hyperactivity was suggested by typical clinical symptoms (i.e. tachycardia, tachypnea, hypertension and hyperhidrosis) associated with elevated plasma catecholamine levels (Cortelli et al., 1991; Montagna et al., 1998; Liguori et al., 2001) but direct evidence of this is lacking. The aim of this study was to investigate sympathetic activity directly by microneurography in three patients with acquired and genetic AE to verify a similar pattern of sympathetic over-activity potentially contributing to the development of cardiovascular dysfunctions and reinforcing the hypothesis of a common pathogenetic mechanism underlying AE of different origin. 2. Methods We describe three patients (two patients with MS and one patient with FFI) showing clinical findings compatible with AE. The two MS patients (62- and 71-years-old-men) complained of progressive cognitive impairment, fatigue, nocturnal insomnia, diurnal drowsiness, hyperhydrosis and gait disorder during the last year. Neurological examination showed temporal spatial disorientation, diffuse fasciculations and myoclonias (spontaneous and evoked by sensory stimuli) and clumsy gait. Electrophysiological study disclosed spontaneous repetitive motor unit action poten-

1388-2457/$36.00 Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2009.04.006

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tials (MUPs) such as doublets, triplets and multiplets, myokymic and neuromyotonic discharges with normal motor and sensory nerve conduction studies. A mediastinal neoplasm was detected in the first patient whereas the other patient had a medullary thyroid carcinoma. Both patients underwent neoplasm ablation and plasma exchange with a partial improvement of symptoms. Both patients had high levels of serum antibodies to voltage-gated potassium channels (VGKC), confirming the acquired paraneoplastic origin of the disease (Liguori et al., 2001). The patient with genetically confirmed FFI was a 45-year-old man with nocturnal insomnia, hyperhydrosis, lower limb weakness, progressive diplopia, memory impairment, impotence and gait ataxia in the last 9 months. Neurological examination showed spontaneous and evoked myoclonias, bilateral dysmetria, slightly diffusely increased tendon reflexes, retropulsion and ataxic gait. No medications affecting autonomic function were taken by the patients. Electrophysiological study disclosed no abnormality in the muscles (right abductor pollicis brevis and left tibialis anterior) and nerves (right median and left tibial) explored. All three patients underwent a polysomnographic study which demonstrated an inability to generate slow-wave sleep. Spindles and delta activity, i.e. the typical EEG aspects of slow-wave sleep, were totally absent. Cardiovascular reflexes in one patient with MS and in the patient with FFI disclosed preserved baroreflex pathway with exaggerated response to sympathoexcitatory manoeuvres (i.e. Valsalva manoeuvre, isometric handgrip and/or cold-face test) in both cases confirming previous data (Cortelli et al., 1991) (Table 1). Technical problems prevented us from performing cardiovascular reflexes in the second MS patient. 2.1. Microneurography recordings The recordings were performed 3–5 h after a light meal. Tobacco, caffeine and alcohol were not allowed for 12 h before the examination. The experimental procedures were carefully explained to the subjects and relatives who gave their written informed consent to the study. Subjects were semi-reclining in a comfortable chair. ECG was recorded via Ag–AgCl electrodes on the chest and respiratory movements were monitored by a strain gauge belt around the lower part of the chest. Arterial finger blood pressure was measured non-invasively by the volume-clamp method (Finometer model, Arnhem, The Netherlands), with the cuffs around the middle phalanx of the third finger on the same side as the microneurography recording. Multiunit efferent post-ganglionic muscle sympathetic nerve activity (MSNA) was recorded with an insulated tungsten microelectrode with a tip diameter of a few microns inserted into the left peroneal nerve, posterior to the fibular head. A low-impedance reference electrode was inserted subcutaneously a few centimetres away. The nerve signal was amplified (50,000), filtered (band pass 700–2000 Hz) and fed through a discriminator for further noise reduction and audio-monitoring. A mean voltage (integrated) display was obtained by passing the original signal through a resistance-capacitance circuit (time constant 0.1 s). During the experiment, neural activity and arterial pressure were monitored on a storage oscilloscope. When a muscle nerve fascicle had been identified, small electrode adjustments were made until a site was found in which sympathetic impulses with a good signal-tonoise ratio could be recorded. A recording of MSNA was considered acceptable when it revealed spontaneous, pulse-synchronous bursts of neural activity that fulfilled the criteria for MSNA, previously described (Sundlöf and Wallin, 1977). After acquiring a stable recording site, resting MSNA was recorded for 15 min. Sympathetic

bursts occurring during the last 5 min of rest period were identified by inspection of the mean voltage neurogram, and the amount of activity was expressed as burst incidence (bursts/100 heart beats) and burst frequency (bursts/min). Resting arterial blood pressure (BP) was measured sphygmomanometrically, 10 min before the start of the recording with the subjects in a semi-reclining position. The filtered and integrated nerve signals were sampled and stored together with other signals in a personal computer using a locally produced data acquisition system. In addition, all signals were stored on analogue tape. Fifteen age-matched healthy males (57 ± 13 years) without clinical signs of neurological dysfunctions served as controls. 3. Results MSNA was always recorded in the control subjects and the mean activity was 56 ± 18 bursts/100 heart beats (HB) and 36 ± 12 bursts/min with the highest value obtained of 78 bursts/ 100 heart beats and 56 bursts/min. Sympathetic activity showed normal cardiac rhythmicity and was strictly coupled to blood pressure oscillations mainly occurring during blood pressure reduction. The mean level of heart rate (HR) was 64 ± 10 beats/min, whereas mean value of BP was 130 ± 15 and 80 ± 8 for systolic and diastolic BP, respectively (Table 1). During microneurography patients were probably awake since they did not present the enacted dreams typical of sleep or reduced level of vigilance (i.e. drowsiness). The mean level of MSNA activity was higher in patients than controls (96 ± 3 and 77 ± 6 bursts/100 HB and bursts/min respectively). According to Z-statistics each patient presented significantly higher MSNA values than controls (Fig. 1 and Table 1). In addition, all three patients showed a sympathetic over-activation with a sympathetic burst expressed in approximately each cardiac beat but with a still maintained cardiac rhythmicity (Fig. 1). Similarly, HR was higher in patients than controls (81 ± 10 beats/min) and the Z-statistics disclosed a significant increase in two patients (Table 1). BP was higher in patients (145 ± 9 and 87 ± 6 for systolic and diastolic BP) compared to controls but a significant systolic BP increase was evident in one subject only (Table 1). 4. Discussion The concept of AE was recently proposed as including loss of slow-wave sleep (SWS), mental oneirism and marked motor and autonomic activation (Liguori et al., 2001; Lugaresi and Provini, 2001; Montagna and Lugaresi, 2002). AE is shared by apparently different diseases such as DT, MS, MSS and FFI. There is clinical and neurophysiological evidence in favour of AE as a concept unifying the sleep disturbances in these diseases. All conditions are characterized by insomnia and secondary drowsiness associated with dreaming behaviour consisting of complex and organized, sometimes well-structured hallucinations which are enacted in a purposeful way. Polysomnographic recordings showed that these conditions are characterized by the inability to generate the sleep rhythms typical of deep sleep, e.g. delta activity, and those transitional EEG figures – sleep spindles and K complexes – which characterize the physiological transition from wake to sleep (Montagna and Lugaresi, 2002). Other important common clinical characteristics of AE are the motor hyperactivity that may last throughout the 24 h (Lugaresi and Provini, 2001) and the autonomic hyperactivity with tachycardia, tachypnea, hypertension, fever and hyperhydrosis. As in our cases, the sympathetic over-activation was suggested by the exaggerated response to sympathoexcitatory manoeuvres during the

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V. Donadio et al. / Clinical Neurophysiology 120 (2009) 1139–1142 Table 1 Clinical and autonomic data. Age

Diagnosis

MSNA

HR

Syst BP

Bursts/100 HB

Bursts/ min

Beats/ min

mmHg

Diast BP mmHg

Cardiovascular reflexes Tilt test

Valsalva

Deep breath

Isometric handgrip

Cold face test

71

Acquired AE (MS)

98*

69*

71+

155**

90+

Normal

Normal

Normal

Normal

Hypertension

62

Acquired AE (MS)

90*

82*

91*

140+

90+

ND

ND

ND

ND

ND

45

Genetic AE (FFI)

100*

81*

81**

140+

80+

Normal

Exaggerated overshoot

Normal

Hypertension

Normal

57 ± 13

Controls

56 ± 18

36 ± 12

64 ± 10

130 ± 15

80 ± 8

AE, Agrypnia Excitata; MS, Morvan’s syndrome; FFI, fatal familial insomnia; MSNA, muscle sympathetic nerve activity; HR, heart rate; BP, blood pressure; ND, not done. * Z score > 2.3 p < 0.01. ** Z score = 1.7 p < 0.05. + Z score < 1.7 p > 0.05.

evaluation of cardiovascular reflexes (Cortelli et al., 1991). This conclusion was also suggested by elevated plasma cathecolamine levels (Cortelli et al., 1991; Montagna et al., 1998; Liguori et al., 2001) although recent data reported a poor reproducibility of plasma cathecolamines which is lower than a direct measurement of the efferent postganglionic MSNA recorded by microneurography (Grassi et al., 2008a,b). Our AE patients underwent the first microneurographic recordings of MSNA to verify the sympathetic over-activity disclosed by indirect tests of sympathetic function and suggested by the exaggerated sympathetic activation during several manoeuvres. Our data confirmed that AE patients presented resting awake sympathetic over-activity with significantly raised MSNA and HR compared to controls. Increased MSNA was likely not related to sleep. We did not measure the level of vigilance by electroencephalography (EEG) during microneurography but we can draw this conclusion because in this disorder sleep or reduced level of vigilance (i.e. drowsiness) are typically associated with enacted dreams which were not seen during our recordings. Patients with AE of different origin (i.e. acquired and genetic) showed a similar patter of sympathetic over-activity with a sympathetic burst expressed in approximately each cardiac beat suggesting a common pathogenetic mechanism underlying AE. Several clinical and experimental findings support the contention that AE has a distinct anatomical substrate in the dysfunction of the thalamo-limbic system producing a functional disconnection of the hypothalamus, brainstem and basal forebrain (Lugaresi et al., 1998). In FFI, the marked and selective atrophy of the mediodorsal and anteroventral thalamic nuclei has been considered to underlie the alterations of sleep and the characteristic autonomic and circadian abnormalities (Lugaresi et al., 1998). In MS, a direct effect of the VGKC antibodies on the thalamus and limbic system was demonstrated, probably responsible for the impairment of the cortico-

limbic control over the subcortical structures regulating the sleep–wake and autonomic functions (Liguori et al., 2001). The scant pathological evidence available to date in DT also points to a dysfunction in the diencephalic structures, hypothalamus, mammillo-thalamic tracts and thalamus. An accumulation of antibodies (MS) or sudden alcohol withdrawal (DT) may affect the (probably GABAergic) inhibitory synapses of the thalamo-limbic system, thus inducing a transient prevalence of excitatory hypothalamic structures (Lugaresi et al., 1998; Liguori et al., 2001). In line with this evidence, we consider that the sympathetic over-activation in AE may stem from an exaggerated sympathetic drive of some supramedullary structures, such as the dorsomedial hypothalamic areas (Benarroch and Stotz-Potter, 1998). These brain structures released from the inhibitory control exerted by the thalamo-limbic system, could lead to an altered equilibrium state with a prevalence of ‘ergotropic’ (arousing) activities, aimed at energy expenditure and behavioural activity (Hess, 1944; Parmeggiani, 1964; Gritti et al., 1998; Lugaresi et al., 1998). This hypothesis is supported by the finding of preserved brainstem autonomic reflexes (i.e. baroreflex pathway) in our patients and in a previous report (Cortelli et al., 1993). Furthermore, the medial thalamus belongs to the central autonomic network (CAN) involved in the regulation of vegetative functions. Indeed, kainic acid lesions of the medial thalamus in the rat cause persistent hypertension and the administration of bicuculline, an antagonist of the inhibitory neurotransmitter GABA, into the medial thalamus elicits an increase in arterial pressure and heart rate in rabbits (Benarroch and Stotz-Potter, 1998). On the other hand, the increased sympathetic activity may not be simply explained by the insomnia as sleep deprivation was described to decrease MSNA (Ogawa et al., 2003; Kato et al., 2000). Our patients showed higher BP than controls (mean increase of 15 mmHg for systolic and 7 mmHg for diastolic BP) which was significant in one patient. Taken together our data may suggest that

Fig. 1. Mean voltage neurogram in a sex and age-matched healthy control (A) and in two patients with genetic AE (FFI) (B) and acquired AE (MS) (C). Patients presented a sympathetic over-activation with significantly MSNA increase compared to control. The degree of sympathetic increase is similar in both patients who showed a sympathetic burst expressed in approximately each cardiac beat.

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sympathetic over-activity could be responsible for the increase in blood pressure and predispose to hypertension and cardiovascular dysfunctions occurring in AE. In this regard sympathoexcitation may have a prognostic relevance as it significantly influences the morbility/mortality of the underlying disorder (Barretto et al., 2008; Smith et al., 2004; Elam, 2003). In conclusion, our data demonstrate that acquired and genetic AE presented a comparable sympathetic over-activity including high resting MSNA and HR. While this confirms that a common pathogenetic mechanism underlies AE, it probably reflects an abnormal activation of the diencephalic structures such as the hypothalamus. Furthermore, our data pointed out that AE patients may develop high blood pressure and/or cardiovascular instability potentially increasing the morbility/mortality of the underlying disorders. Competing interests None. References Barretto AC, Santos AC, Munhoz R, Rondon MU, Franco FG, Trombetta IC, et al. Increased muscle sympathetic nerve activity predicts mortality in heart failure patients. Int J Cardiol 2008 [Epub ahead of print]. Benarroch EE, Stotz-Potter EH. Dysautonomia in fatal familial insomnia as an indicator of the potential role of the thalamus in autonomic control. Brain Pathol 1998;8:527–30. Cortelli P, Parchi P, Contin M, Pierangeli G, Avoni P, Tinuper P, et al. Cardiovascular dysautonomia in fatal familial insomnia. Clin Auton Res 1991;1:15–21. Elam M. Cardiac neural discharge preceding sudden death: efferent, afferent or both? Clin Auton Res 2003;13:314–5. Ferri R, Lanuzza B, Cosentino FI, Iero I, Russo N, Tripodi M, et al. Agrypnia Excitata in a patient with progeroid short stature and pigmented Nevi (Mulvihill–Smith syndrome). J Sleep Res 2005;14:463–70. Grassi G, Bolla GB, Seravalle G, Quarti-Trevano F, Facchetti R, Mancia G. Multiple sampling improves norepinephrine reproducibility in essential hypertension: a

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