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Autonomic dysfunction in cases of spinal muscular atrophy type 1 with long survival
Brain & Development 27 (2005) 574–578 www.elsevier.com/locate/braindev
Original article
Autonomic dysfunction in cases of spinal muscular atrophy type 1 with long survival Yasuo Hachiyaa,*, Hidee Araib, Masaharu Hayashic, Satoko Kumadad, Wakana Furushimae, Eiko Ohtsukaf, Yasushi Itof, Akira Uchiyamaa, Kiyoko Kurataa a
Department of Pediatrics, Tokyo Metropolitan Fuchu Medical Center for SMID, 2-9-2 Musashi-dai, Fuchu-shi, Tokyo 183-0042, Japan b Department of Pediatrics, National Hospital Organization, Chiba Medical Center, Chiba, Japan c Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan d Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan e Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan f Department of Pediatrics, Tokyo Women’s Medical College, Tokyo, Japan Received 22 November 2004; received in revised form 3 February 2005; accepted 21 February 2005
Abstract In Japan, quite a few patients with spinal muscular atrophy type 1 (SMA type 1) survive with mechanical ventilation. Since a patient with SMA type 1 and continuous artificial ventilation exhibited excessive perspiration and tachycardia, we examined the autonomic functions in three cases of SMA type 1, undergoing mechanical ventilation. Two cases exhibited the common sympathetic-vagal imbalance on R–R interval analysis involving 24-h Holter ECG recordings in addition to an abnormality in finger cold-induced vasodilatation. Furthermore, one case showed blood pressure and heart rate fluctuation with the paroxysmal elevation, and a high plasma concentration of norepinephrine during tachycardia. These findings suggest that autonomic dysfunction should be examined in SMA type 1 patients with long survival, although the pathogenesis remains to be clarified. q 2005 Elsevier B.V. All rights reserved. Keywords: Autonomic dysfunction; Epinephrine; Heart rate; Long survival; MIBG; Respirator; R–R interval; Spinal muscular atrophy type 1
1. Introduction Spinal muscular atrophy type 1 (SMA type 1) is a hereditary neurodegenerative disease, with progressive muscular weakness and atrophy, due to the degeneration of motor neurons in the spinal cord and/or brainstem [1,2]. The genes responsible for three clinically and genetically distinct forms of autosomal recessive SMA, i.e. Werdnig-Hoffmann disease (type 1), intermediate form (type 2), and KugelbergWelander disease (type 3), are mapped to chromosome 5q13. The survival motor neuron gene (smn) is deleted in more than 90% of SMA patients, in addition to deletion of the gene of another neuronal apoptosis inhibitory protein (naip) located near the smn gene [1]. Amyotrophic lateral sclerosis (ALS) is
an adult-onset neurodegenerative disease involving the motor neuron system, in which autonomic dysfunction can occur more frequently than previously expected [3,4]. Although autonomic disturbances have rarely been observed in SMA type 1, we recently experienced a SMA type 1 patient with continuous artificial ventilation that exhibited excessive perspiration and a bout of tachycardia. Here, we examine the autonomic functions in three SMA type 1 patients with long survival under artificial ventilation and discuss the involvement of the autonomic nervous system in child-onset motor neuron diseases.
2. Materials and methods 2.1. Subjects
* Corresponding author. Tel.:C81 42 323 5115; fax: C81 42 322 6207. E-mail address: [email protected] (Y. Hachiya).
0387-7604/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2005.02.009
The subjects were three patients with clinico-genetically confirmed SMA1, consisting of brothers aged nine years (case 1) and six years (case 2), respectively, and
Y. Hachiya et al. / Brain & Development 27 (2005) 574–578 Table 1 Summary of clinical features SMA patients
1
2
3
Norepinephrine (pg/ml)/ Epinephrine (pg/ml) wake time sleep time paroxysmal tachycardia wake time at rest HF (ms2) 24h LF/HF (ms2) 24h
231/138 188/9 749/196 529/179 318.6 3.17
264/100 205/218 ND ND 571.6 1.25
325/29 ND ND 183/627 96.3 3.25
a six-year-old girl (case 3) (Table 1). All patients had never acquired head control, generalized muscle hypotonia and weakness led to the clinical diagnosis, and genetic analysis confirmed the deletion of smn but not of naip. Only case 1 underwent a muscle biopsy, which demonstrated a severe neurogenic change. All patients had required persistent artificial respiration due to progressive paralysis of the respiratory muscles around the age of 7 months. Only case 1 suffered from paroxysmal sinus tachycardia associated with transient hypertension on arousal in the absence of any inducement. Case 2 had suffered from several mild hypoxic events due to repetitive epileptic seizures, and brain magnetic resonance imaging (MRI) showed mild cerebral atrophy in the frontal lobe (data not shown). On the other hand, brain MRI revealed no abnormalities in case 1, and a thalamic change in case 3 [5], respectively. Short latency somatosensory-evoked potentials after stimulation of the median nerve (SSEP) demonstrated the lack of late wave components N18 and N20 in case 1, and that of components N11-20 in case 2, respectively, while they were not examined in case 3. Each autonomic test was performed once. 2.2. Measurement of blood pressure, heart rate, and plasma catecholamine for 24 h In all subjects, a 24-gauge Teflon catheter was inserted into a superficial vein in the arm, which was kept in place with a heparin lock for blood sampling. Blood pressure and heart rate were recorded using an automatic sphygmomanometer (Nihon-Koden, Tokyo, Japan) for 24 h at 30–60 min intervals from 8:00 to 20:00, and 60 min intervals from 20:00–8:00. Measurement of blood pressure and heart rate, and blood sampling started at 16:00 and finished at 16:00 on the next day. Blood was made to flow into the catheter backwards and sampled in the resting period at the time of arousal and 3:00 in addition to the time when paroxysmal sinus tachycardia with hypertension occurred. For the 24 h examination, all subjects were kept in the supine position. Tube feeding was performed at 6:00, 12:00, 18:00, and 21:00 in cases 1 and 2. On the other hand, case 3 received periodic tube feeding at 6:00 and 12:00, whereas it was continuously given from 16:00 to 21:00 for episodes of hypoglycemia in the evening. No case exhibited disturbance
575
of the sleep–wake cycle, and the lights were put off at 21:00. Power-spectral analysis of R–R intervals was performed to obtain low-frequency (LF) components, high-frequency (HF) components, and LF/HF, using a Holter recorder (SM-30; Fukuda-Denshi, Tokyo, Japan). We referred to the literature for data for normal Japanese children [6]. Blood was collected in a tube containing EDTA and immediately placed on ice. Plasma was separated within 15 min in a centrifuge (3000 g for 10 min at 4 8C), and then frozen at K80 8C until assaying. Plasma epinephrine and norepinephrine were measured by high-performance liquid chromatography with an HLC8030, an automatic catecholamine analyzer (Tosoh Co., Ltd., Tokyo, Japan). 2.3. Head-up tilting To study the cardiovascular response to a passive change in posture, head-up tilting was performed in cases 1 and 3. Blood pressure and heart rate were recorded using an automatic sphygmomanometer, and blood samples were obtained during the head-up tilting by the aforementioned method. After 5 min in the supine position, we started measurement of blood pressure and heart rate at 1 min intervals, and after 10 min the table was tilted to a 55– 608head-up position. The subjects were kept in this head-up position for 25 min. Baseline blood samples were drawn from the indwelling Teflon catheter at rest 30 min after cannulation to avoid elevation of norepinephrine. Blood sampling was carried out at 5 and 20 min after the head-up tilting to assay norepinephrine and epinephrine. 2.4. Finger cold-induced vasodilatation The finger-skin temperature was used to determine finger cold-induced vasodilatation. The thermometer was placed on the inner side of the right index finger with an insulation pad. The skin temperature was measured every 30 s before immersion for 5 min, during immersion in ice water for 15 min, and after immersion for 10 min. The skin temperature results are depicted graphically in figures. The test was performed at 25–30 8C in a quiet room when the subjects were awake. 2.5. Cardiac MIBG SPECT In order to evaluate myocardial noradrenergic activity and innervation, the uptake and washout dynamics of [123I]-meta-iodobenzyl-guanidine (123I-MIBG) were analyzed in case 1. The dose of 75MBq 123I-MIBG was injected. MIBG uptake was measured 15 min and 3 h after its administration, and the washout rate was determined using the relative decrease in cardiac activity. We chose rectangular regions of interest (ROI), including of the left ventricle and the mediastinum. Relative myocardial MIBG uptake was computed after normalization in comparison to that in the mediastinum. Cardiac MIBG uptake was
576
Y. Hachiya et al. / Brain & Development 27 (2005) 574–578
Blood pressure and heart rate
bpm mmHg
160 HR
140 120 SBP
100 80 60
DBP
40 20 0
16
20
24
4 Time (hours)
8
12
16
Fig. 1. The results of measurement of blood pressure (closed rhomboids), heart rate (open circles), and plasma catecholamine for 24 h in case 1. Remarkable fluctuation of blood pressure and heart rate was observed. Abbreviations: bpm, beats per minute; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure.
expressed as the heart/ mediastinum ratio (H/M ratio). The washout rate was calculated as [(early averaged heart pixel count—early averaged mediastinal pixel count)— (delayed averaged heart pixel count—delayed averaged mediastinal pixel count)]/(early averaged heart pixel count—early averaged mediastinal pixel count).
pressure and heart rate being shown in Fig. 1. Case 1 exhibited elevation of blood pressure along with the daytime paroxysmal tachycardia, which was followed by rapid recovery of the blood pressure and heart rate. On the other hand, the blood pressure and heart rate fluctuation was milder in cases 2 and 3. None of the cases showed any other autonomic changes, including sudoresis, lacrimation, mydriasis, and salivation during the measurement. The LF/HF ratio, an indicator of the sympatho-vagal balance or sympathetic activity, increased in cases 1 and 3, whereas HF, an indicator of parasympathetic nerve activity, was preserved in all cases, being comparable to the data for healthy subjects (LF/HF, 1.37G0.64; HF, 863G880) cited in the previous literature (Table 2) [6]. In case 1, the plasma concentration of norepinephrine was increased at the time of paroxysmal tachycardia with elevation of blood pressure, and remained high even after the fit had finished. But a high concentration of norepinephrine was not constantly observed in case 1. The concentration of epinephrine also exhibited a mild increase during and several hours after the attack. The plasma concentrations of norepinephrine and epinephrine were within normal range, i.e. 100–450 pg/ml and under 100 pg/ml, respectively, at the time of the diurnal monitoring of the heart rate and blood pressure in all cases. 3.2. Head-up tilting
3. Results 3.1. Measurement of blood pressure, heart rate, and plasma catecholamine for 24 h Case 1 exhibited remarkable fluctuation of blood pressure and heart rate, the diurnal changes of blood
Since cases 1 and 3 exhibited common disturbances on R–R interval analysis, head-up tilting was additionally performed in these two cases. Neither case exhibited an abnormal response of either blood pressure or heart rate during the tilting. However, the concentrations of plasma norepinephrine and epinephrine continued to be high,
Table 2 Summary of the results of plasma catecholamine analysis and power-spectral analysis in three SMA 1 patients Norepinephrine (pg/ml) Case
1 2 3 Controls Epinephrine (pg/ml) Case 1 2 3 Controls
Power-spectral analysis
24 h-recording Wake time
Sleep time
231 264 ND
188 205 325
24 h-recording Wake time 138 100 ND
Sleep time 9 218 29
Paroxysmal tachycardia
Wake time at rest
LF/HF (24 h, ms2)
HF (24 h, ms2)
749 ND ND
529 ND ND 100–450
3.17 1.25 3.25 1.37G0.64
318.6 571.6 96.3 863G880
Paroxysmal tachycardia
Wake time at rest
196 ND ND
179 ND ND !100
In case 1, the plasma concentration of norepinephrine was increased at the time of paroxysmal tachycardia and remained high even after the fit had finished. The LF/HF ratio was increased in all cases. LF/HF was calculated using the data obtained on 24 h-Holter ECG. Abbreviations: ND, not determined; LF, lowfrequency components; HF, high-frequency components.
Y. Hachiya et al. / Brain & Development 27 (2005) 574–578 bpm mmHg
Blood pressure and heart rate
160
HR tilt
140 120 100
SBP
80 60 40
DBP
20 E/NE 122/528
223/867
201/937
0 -5
0
5
10 Time
15
20
25 min
Fig. 2. Head-up tilting in case 1. Case 1 exhibited no abnormal response of either blood pressure (closed rhomboids) or heart rate (open circles) during head-up tilting, although the concentrations of plasma norepinephrine and epinephrine continued to be high. Abbreviations: bpm, beats per minute; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; E, epinephrine; NE, norepinephrine.
ranging from 500 to 900 pg/ml, and between 100 and 200 pg/ml, respectively, during the tilting in case 1 but not in case 3 (Fig. 2). 3.3. Finger cold-induced vasodilatation In normal subjects, the skin temperature quickly falls to 8–15 8C, rises to about 17–25 8C 6–7 min after the start of immersion, reflecting cold-induced vasodilatation, and then fluctuates (hunting reaction) [7,8]. Cessation of immersion causes a prompt recovery of the skin temperature. All cases exhibited a rapid decrease and subsequent increase in skin temperature. However, in cases 1 and 3, the extent of the decrease was reduced, and the hunting reaction was absent. In addition, case 1 showed delayed recovery of the skin temperature after the cessation of immersion. 3.4. Cardiac MIBG SPECT Cardiac SPECT was performed in case 1, because he showed severe autonomic abnormalities. His delayed H/M ratio (2.17) and washout-ratio (22.9%) were well preserved, being comparable to those of normal subjects (2–3 and 14–30%, respectively) cited in the literature [9–11].
4. Discussion SMA type 1 cases 1 and 3 exhibited increased LF/HF ratios and abnormalities in finger cold-induced vasodilatation. Case 1 showed additional autonomic abnormalities, including fluctuation of blood pressure and heart rate with the paroxysmal soaring, and a high plasma concentration of
577
norepinephrine during both the tachycardia and tilting, whereas he did not exhibit any other autonomic symptoms during the measurement, and the cardiac MIBG SPECT parameters were normal. Only case 3 had excessive perspiration as an obvious autonomic symptom (Table 1). So, the various abnormalities observed in the autonomic function tests appeared to be in accordance with the clinical autonomic disturbances in cases 1 and 3. Also, all these data suggest sympathetic hyperactivity, reduced baroreflex sensitivity and/or a sympathetic-vagal imbalance. But we performed each test only once because repetitive challenges were neither possible for the physical status of the cases nor granted by their patients. It is noteworthy that the brothers, i.e. cases 1 and 2, showed a striking contrast in autonomic function test results. The older brother showed various disturbances, whereas the younger brother showing mild cerebral atrophy on MRI exhibited no changes in addition to the lack of clinical autonomic disturbances. The cause of the difference between the brothers could not be determined through this analysis, but further involvement of sensory nervous system suggested by the SSEP abnormalities might be related to the autonomic dysfunctions in case 1. In the spinal cord, it is well known that the lumbar and sacral intermediolateral nuclei, and the sacral Onufrowicz’s nucleus can be involved in sympathetic and parasympathetic neuron systems. Although several neurons in the sacral Onufrowicz’s nucleus exhibit central chromatolysis, the neurons of the sacral intermediolateral nuclei are relatively well preserved in SMA type 1 [12,13]. On the other hand, the relative areas of neural tissue in the myenteric plexus of the small intestine and colon were significantly lower in SMA type 1 than in controls [14]. Thus, pathological evaluation of the autonomic nervous system has not led to a definitive conclusion concerning SMA type 1. However, it should be considered that mechanical ventilation has allowed our cases to survive, the expected life span of SMA type 1 patients being exceeded. Japanese research groups have reported that longsurviving ALS patients on a respirator develop similar disturbances of the autonomic nervous system, i.e. attacks of severe hypertension and tachycardia, marked blood pressure fluctuation, and a high plasma concentration of norepinephrine [3,4]. Also, they pointed out the possibility that the sympathetic hyperactivity can cause circulatory collapse or sudden death in respirator-dependent ALS. Although the pathophysiology of sympathetic hyperactivity has not been fully elucidated in ALS patients, the involvement of the central autonomic network is speculated. In some cases of SMA type 1, lesions in the posteroventral thalamic nuclei, Clarke’s column and spinal ganglion have been pathologically verified [2]. In case 3, we previously reported neuroradiological and neurophysiological changes in the thalamus, i.e. high signal intensity in T2-weighted images on brain magnetic resonance imaging and altered spindles on electoroencephalography, although she
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Y. Hachiya et al. / Brain & Development 27 (2005) 574–578
exhibited no sensory disturbances and SSEP were not examined [5]. Several nuclei of the thalamus are known to interconnect with other brain regions and to thereby control autonomic functions [15]. The presence of a latent thalamic lesion may suggest the possibility of involvement of the central autonomic network in SMA type 1 like in ALS. A latent thalamic lesion is also possible in case 1 showing the lack of thalamic components of SSEP, although MRI failed to detect any thalamic changes. Since sustained mechanical ventilation support for SMA type 1 patients has long been practiced in Japan [16] and autonomic disturbances seem to occur more frequently than previously considered, we believe that the detailed analysis of autonomic functions is a prerequisite for improving the quality of life of longsurviving SMA type 1 patients.
References [1] Schmalbruch H, Haase G. Spinal muscular atrophy: present state. Brain Pathol 2001;11:231–47. [2] Osawa M, Shishikura K. Werdnig-Hoffmann disease and variants. In: de Jong JMBV, editor. Handbook of clinical neurology. Handbook of clinical neurology, vol. 15. New York: Elsevier; 1991. p. 51–80. [3] Shimizu T, Kato S, Hayashi M, Hayashi H, Tanabe H. Amytrophic lateral sclerosis with hypertensive attacks: blood pressure changes in response to drug administration. Clin Auton Res 1996;6:241–4. [4] Ohno T, Shimizu T, Kato S, Hayashi H, Hirai S. Effect of tamsulosin hydrochloride on sympathetic hyperactivity in amytrophic lateral sclerosis. Auton Neurosci 2001;88:94–8. [5] Ito Y, Kumada S, Uchiyama U, Saito K, Osawa M, Yagishita A, et al. Thalamic lesion in a long-surviving child with spinal muscular atrophy type I: MRI and EEG findings. Brain Dev 2004;26:53–6.
[6] Kazuma N, Otsuka K, Wakamatsu K, Shirase E, Matsuoka I. Heart rate variability in normotensive healthy children with aging. Clin Exp Hypertens 2002;24:83–9. [7] Daanen HA. Finger cold-induced vasodilatation: a review. Eur J Appl Physiol 2003;89:411–26. [8] Sendowski I, Savourey G, Launay JC, Besnard Y, Cottet-Emard JM, Pequignot JM, et al. Sympathetic stimulation induced by hand cooling alters cold-induced vasodilatation in humans. Eur J Appl Physiol 2000;81:303–9. [9] Sakamaki F, Satoh T, Nagaya N, Kyotani S, Oya H, Nakanishi N, et al. Correlation between severity of pulmonary arterial hypertension and 123I-metaiodobenzylguanidine left ventricular imaging. J Nucl Med 2000;41:1127–33. [10] Maunoury C, Agostini D, Acar P, Antonietti T, Sidi D, Bouvard G, et al. Impairment of cardiac neuronal function in childhood dilated cardiomyopathy: an 123I-MIBG scintigraphic study. J Nucl Med 2000; 41:400–4. [11] Momose M, Kobayashi H, Kasanuki H, Kusakabe K, Tamaki A, Onishi S, et al. Evaluation of regional cardiac sympathetic innervation in congenital long QT syndrome using 123I-MIBG scintigraphy. Nucl Med Commun 1998;19:943–51. [12] Chou SM, Kuzuhara S, Nonaka I. Involvement of the Onuf nucleus in Werdnig-Hoffmann disease. Neurology 1982;32:880–4. [13] Sung JH, Mastri AR. Spinal autonomic neurons in Werdnig-Hoffmann disease, mannosidosis, and Hurler’s syndrome: distribution of autonomic neurons in the sacral spinal cord. J Neuropathol Exp Neurol 1980;39:441–51. [14] Galvis DA, Ang SM, Wells TR, Landing BH, Romansky SG. Microdissection study of the myentric plexus in acardia, ataxiatelangiectasia, cystic fibrosis, extrahepatic biliary atresia, pediatric AIDS and Werdnig-Hoffmann disease. Pediatr Pathol 1992;12: 385–95. [15] Benarroch EE. Functional anatomy of the central autonomic nervous system. In: Davis KE, editor. Handbook of clinical neurology. Handbook of clinical neurology, vol. 30. New York: Elsevier; 1999. p. 53–86. [16] Sakakihara Y, Kubota M, Kim S, Oka A. Long-term ventilator support in patients with Werdnig-Hoffmann disease. Pediatr Int 2000;42: 359–63.
Original article
Autonomic dysfunction in cases of spinal muscular atrophy type 1 with long survival Yasuo Hachiyaa,*, Hidee Araib, Masaharu Hayashic, Satoko Kumadad, Wakana Furushimae, Eiko Ohtsukaf, Yasushi Itof, Akira Uchiyamaa, Kiyoko Kurataa a
Department of Pediatrics, Tokyo Metropolitan Fuchu Medical Center for SMID, 2-9-2 Musashi-dai, Fuchu-shi, Tokyo 183-0042, Japan b Department of Pediatrics, National Hospital Organization, Chiba Medical Center, Chiba, Japan c Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan d Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan e Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan f Department of Pediatrics, Tokyo Women’s Medical College, Tokyo, Japan Received 22 November 2004; received in revised form 3 February 2005; accepted 21 February 2005
Abstract In Japan, quite a few patients with spinal muscular atrophy type 1 (SMA type 1) survive with mechanical ventilation. Since a patient with SMA type 1 and continuous artificial ventilation exhibited excessive perspiration and tachycardia, we examined the autonomic functions in three cases of SMA type 1, undergoing mechanical ventilation. Two cases exhibited the common sympathetic-vagal imbalance on R–R interval analysis involving 24-h Holter ECG recordings in addition to an abnormality in finger cold-induced vasodilatation. Furthermore, one case showed blood pressure and heart rate fluctuation with the paroxysmal elevation, and a high plasma concentration of norepinephrine during tachycardia. These findings suggest that autonomic dysfunction should be examined in SMA type 1 patients with long survival, although the pathogenesis remains to be clarified. q 2005 Elsevier B.V. All rights reserved. Keywords: Autonomic dysfunction; Epinephrine; Heart rate; Long survival; MIBG; Respirator; R–R interval; Spinal muscular atrophy type 1
1. Introduction Spinal muscular atrophy type 1 (SMA type 1) is a hereditary neurodegenerative disease, with progressive muscular weakness and atrophy, due to the degeneration of motor neurons in the spinal cord and/or brainstem [1,2]. The genes responsible for three clinically and genetically distinct forms of autosomal recessive SMA, i.e. Werdnig-Hoffmann disease (type 1), intermediate form (type 2), and KugelbergWelander disease (type 3), are mapped to chromosome 5q13. The survival motor neuron gene (smn) is deleted in more than 90% of SMA patients, in addition to deletion of the gene of another neuronal apoptosis inhibitory protein (naip) located near the smn gene [1]. Amyotrophic lateral sclerosis (ALS) is
an adult-onset neurodegenerative disease involving the motor neuron system, in which autonomic dysfunction can occur more frequently than previously expected [3,4]. Although autonomic disturbances have rarely been observed in SMA type 1, we recently experienced a SMA type 1 patient with continuous artificial ventilation that exhibited excessive perspiration and a bout of tachycardia. Here, we examine the autonomic functions in three SMA type 1 patients with long survival under artificial ventilation and discuss the involvement of the autonomic nervous system in child-onset motor neuron diseases.
2. Materials and methods 2.1. Subjects
* Corresponding author. Tel.:C81 42 323 5115; fax: C81 42 322 6207. E-mail address: [email protected] (Y. Hachiya).
0387-7604/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2005.02.009
The subjects were three patients with clinico-genetically confirmed SMA1, consisting of brothers aged nine years (case 1) and six years (case 2), respectively, and
Y. Hachiya et al. / Brain & Development 27 (2005) 574–578 Table 1 Summary of clinical features SMA patients
1
2
3
Norepinephrine (pg/ml)/ Epinephrine (pg/ml) wake time sleep time paroxysmal tachycardia wake time at rest HF (ms2) 24h LF/HF (ms2) 24h
231/138 188/9 749/196 529/179 318.6 3.17
264/100 205/218 ND ND 571.6 1.25
325/29 ND ND 183/627 96.3 3.25
a six-year-old girl (case 3) (Table 1). All patients had never acquired head control, generalized muscle hypotonia and weakness led to the clinical diagnosis, and genetic analysis confirmed the deletion of smn but not of naip. Only case 1 underwent a muscle biopsy, which demonstrated a severe neurogenic change. All patients had required persistent artificial respiration due to progressive paralysis of the respiratory muscles around the age of 7 months. Only case 1 suffered from paroxysmal sinus tachycardia associated with transient hypertension on arousal in the absence of any inducement. Case 2 had suffered from several mild hypoxic events due to repetitive epileptic seizures, and brain magnetic resonance imaging (MRI) showed mild cerebral atrophy in the frontal lobe (data not shown). On the other hand, brain MRI revealed no abnormalities in case 1, and a thalamic change in case 3 [5], respectively. Short latency somatosensory-evoked potentials after stimulation of the median nerve (SSEP) demonstrated the lack of late wave components N18 and N20 in case 1, and that of components N11-20 in case 2, respectively, while they were not examined in case 3. Each autonomic test was performed once. 2.2. Measurement of blood pressure, heart rate, and plasma catecholamine for 24 h In all subjects, a 24-gauge Teflon catheter was inserted into a superficial vein in the arm, which was kept in place with a heparin lock for blood sampling. Blood pressure and heart rate were recorded using an automatic sphygmomanometer (Nihon-Koden, Tokyo, Japan) for 24 h at 30–60 min intervals from 8:00 to 20:00, and 60 min intervals from 20:00–8:00. Measurement of blood pressure and heart rate, and blood sampling started at 16:00 and finished at 16:00 on the next day. Blood was made to flow into the catheter backwards and sampled in the resting period at the time of arousal and 3:00 in addition to the time when paroxysmal sinus tachycardia with hypertension occurred. For the 24 h examination, all subjects were kept in the supine position. Tube feeding was performed at 6:00, 12:00, 18:00, and 21:00 in cases 1 and 2. On the other hand, case 3 received periodic tube feeding at 6:00 and 12:00, whereas it was continuously given from 16:00 to 21:00 for episodes of hypoglycemia in the evening. No case exhibited disturbance
575
of the sleep–wake cycle, and the lights were put off at 21:00. Power-spectral analysis of R–R intervals was performed to obtain low-frequency (LF) components, high-frequency (HF) components, and LF/HF, using a Holter recorder (SM-30; Fukuda-Denshi, Tokyo, Japan). We referred to the literature for data for normal Japanese children [6]. Blood was collected in a tube containing EDTA and immediately placed on ice. Plasma was separated within 15 min in a centrifuge (3000 g for 10 min at 4 8C), and then frozen at K80 8C until assaying. Plasma epinephrine and norepinephrine were measured by high-performance liquid chromatography with an HLC8030, an automatic catecholamine analyzer (Tosoh Co., Ltd., Tokyo, Japan). 2.3. Head-up tilting To study the cardiovascular response to a passive change in posture, head-up tilting was performed in cases 1 and 3. Blood pressure and heart rate were recorded using an automatic sphygmomanometer, and blood samples were obtained during the head-up tilting by the aforementioned method. After 5 min in the supine position, we started measurement of blood pressure and heart rate at 1 min intervals, and after 10 min the table was tilted to a 55– 608head-up position. The subjects were kept in this head-up position for 25 min. Baseline blood samples were drawn from the indwelling Teflon catheter at rest 30 min after cannulation to avoid elevation of norepinephrine. Blood sampling was carried out at 5 and 20 min after the head-up tilting to assay norepinephrine and epinephrine. 2.4. Finger cold-induced vasodilatation The finger-skin temperature was used to determine finger cold-induced vasodilatation. The thermometer was placed on the inner side of the right index finger with an insulation pad. The skin temperature was measured every 30 s before immersion for 5 min, during immersion in ice water for 15 min, and after immersion for 10 min. The skin temperature results are depicted graphically in figures. The test was performed at 25–30 8C in a quiet room when the subjects were awake. 2.5. Cardiac MIBG SPECT In order to evaluate myocardial noradrenergic activity and innervation, the uptake and washout dynamics of [123I]-meta-iodobenzyl-guanidine (123I-MIBG) were analyzed in case 1. The dose of 75MBq 123I-MIBG was injected. MIBG uptake was measured 15 min and 3 h after its administration, and the washout rate was determined using the relative decrease in cardiac activity. We chose rectangular regions of interest (ROI), including of the left ventricle and the mediastinum. Relative myocardial MIBG uptake was computed after normalization in comparison to that in the mediastinum. Cardiac MIBG uptake was
576
Y. Hachiya et al. / Brain & Development 27 (2005) 574–578
Blood pressure and heart rate
bpm mmHg
160 HR
140 120 SBP
100 80 60
DBP
40 20 0
16
20
24
4 Time (hours)
8
12
16
Fig. 1. The results of measurement of blood pressure (closed rhomboids), heart rate (open circles), and plasma catecholamine for 24 h in case 1. Remarkable fluctuation of blood pressure and heart rate was observed. Abbreviations: bpm, beats per minute; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure.
expressed as the heart/ mediastinum ratio (H/M ratio). The washout rate was calculated as [(early averaged heart pixel count—early averaged mediastinal pixel count)— (delayed averaged heart pixel count—delayed averaged mediastinal pixel count)]/(early averaged heart pixel count—early averaged mediastinal pixel count).
pressure and heart rate being shown in Fig. 1. Case 1 exhibited elevation of blood pressure along with the daytime paroxysmal tachycardia, which was followed by rapid recovery of the blood pressure and heart rate. On the other hand, the blood pressure and heart rate fluctuation was milder in cases 2 and 3. None of the cases showed any other autonomic changes, including sudoresis, lacrimation, mydriasis, and salivation during the measurement. The LF/HF ratio, an indicator of the sympatho-vagal balance or sympathetic activity, increased in cases 1 and 3, whereas HF, an indicator of parasympathetic nerve activity, was preserved in all cases, being comparable to the data for healthy subjects (LF/HF, 1.37G0.64; HF, 863G880) cited in the previous literature (Table 2) [6]. In case 1, the plasma concentration of norepinephrine was increased at the time of paroxysmal tachycardia with elevation of blood pressure, and remained high even after the fit had finished. But a high concentration of norepinephrine was not constantly observed in case 1. The concentration of epinephrine also exhibited a mild increase during and several hours after the attack. The plasma concentrations of norepinephrine and epinephrine were within normal range, i.e. 100–450 pg/ml and under 100 pg/ml, respectively, at the time of the diurnal monitoring of the heart rate and blood pressure in all cases. 3.2. Head-up tilting
3. Results 3.1. Measurement of blood pressure, heart rate, and plasma catecholamine for 24 h Case 1 exhibited remarkable fluctuation of blood pressure and heart rate, the diurnal changes of blood
Since cases 1 and 3 exhibited common disturbances on R–R interval analysis, head-up tilting was additionally performed in these two cases. Neither case exhibited an abnormal response of either blood pressure or heart rate during the tilting. However, the concentrations of plasma norepinephrine and epinephrine continued to be high,
Table 2 Summary of the results of plasma catecholamine analysis and power-spectral analysis in three SMA 1 patients Norepinephrine (pg/ml) Case
1 2 3 Controls Epinephrine (pg/ml) Case 1 2 3 Controls
Power-spectral analysis
24 h-recording Wake time
Sleep time
231 264 ND
188 205 325
24 h-recording Wake time 138 100 ND
Sleep time 9 218 29
Paroxysmal tachycardia
Wake time at rest
LF/HF (24 h, ms2)
HF (24 h, ms2)
749 ND ND
529 ND ND 100–450
3.17 1.25 3.25 1.37G0.64
318.6 571.6 96.3 863G880
Paroxysmal tachycardia
Wake time at rest
196 ND ND
179 ND ND !100
In case 1, the plasma concentration of norepinephrine was increased at the time of paroxysmal tachycardia and remained high even after the fit had finished. The LF/HF ratio was increased in all cases. LF/HF was calculated using the data obtained on 24 h-Holter ECG. Abbreviations: ND, not determined; LF, lowfrequency components; HF, high-frequency components.
Y. Hachiya et al. / Brain & Development 27 (2005) 574–578 bpm mmHg
Blood pressure and heart rate
160
HR tilt
140 120 100
SBP
80 60 40
DBP
20 E/NE 122/528
223/867
201/937
0 -5
0
5
10 Time
15
20
25 min
Fig. 2. Head-up tilting in case 1. Case 1 exhibited no abnormal response of either blood pressure (closed rhomboids) or heart rate (open circles) during head-up tilting, although the concentrations of plasma norepinephrine and epinephrine continued to be high. Abbreviations: bpm, beats per minute; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; E, epinephrine; NE, norepinephrine.
ranging from 500 to 900 pg/ml, and between 100 and 200 pg/ml, respectively, during the tilting in case 1 but not in case 3 (Fig. 2). 3.3. Finger cold-induced vasodilatation In normal subjects, the skin temperature quickly falls to 8–15 8C, rises to about 17–25 8C 6–7 min after the start of immersion, reflecting cold-induced vasodilatation, and then fluctuates (hunting reaction) [7,8]. Cessation of immersion causes a prompt recovery of the skin temperature. All cases exhibited a rapid decrease and subsequent increase in skin temperature. However, in cases 1 and 3, the extent of the decrease was reduced, and the hunting reaction was absent. In addition, case 1 showed delayed recovery of the skin temperature after the cessation of immersion. 3.4. Cardiac MIBG SPECT Cardiac SPECT was performed in case 1, because he showed severe autonomic abnormalities. His delayed H/M ratio (2.17) and washout-ratio (22.9%) were well preserved, being comparable to those of normal subjects (2–3 and 14–30%, respectively) cited in the literature [9–11].
4. Discussion SMA type 1 cases 1 and 3 exhibited increased LF/HF ratios and abnormalities in finger cold-induced vasodilatation. Case 1 showed additional autonomic abnormalities, including fluctuation of blood pressure and heart rate with the paroxysmal soaring, and a high plasma concentration of
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norepinephrine during both the tachycardia and tilting, whereas he did not exhibit any other autonomic symptoms during the measurement, and the cardiac MIBG SPECT parameters were normal. Only case 3 had excessive perspiration as an obvious autonomic symptom (Table 1). So, the various abnormalities observed in the autonomic function tests appeared to be in accordance with the clinical autonomic disturbances in cases 1 and 3. Also, all these data suggest sympathetic hyperactivity, reduced baroreflex sensitivity and/or a sympathetic-vagal imbalance. But we performed each test only once because repetitive challenges were neither possible for the physical status of the cases nor granted by their patients. It is noteworthy that the brothers, i.e. cases 1 and 2, showed a striking contrast in autonomic function test results. The older brother showed various disturbances, whereas the younger brother showing mild cerebral atrophy on MRI exhibited no changes in addition to the lack of clinical autonomic disturbances. The cause of the difference between the brothers could not be determined through this analysis, but further involvement of sensory nervous system suggested by the SSEP abnormalities might be related to the autonomic dysfunctions in case 1. In the spinal cord, it is well known that the lumbar and sacral intermediolateral nuclei, and the sacral Onufrowicz’s nucleus can be involved in sympathetic and parasympathetic neuron systems. Although several neurons in the sacral Onufrowicz’s nucleus exhibit central chromatolysis, the neurons of the sacral intermediolateral nuclei are relatively well preserved in SMA type 1 [12,13]. On the other hand, the relative areas of neural tissue in the myenteric plexus of the small intestine and colon were significantly lower in SMA type 1 than in controls [14]. Thus, pathological evaluation of the autonomic nervous system has not led to a definitive conclusion concerning SMA type 1. However, it should be considered that mechanical ventilation has allowed our cases to survive, the expected life span of SMA type 1 patients being exceeded. Japanese research groups have reported that longsurviving ALS patients on a respirator develop similar disturbances of the autonomic nervous system, i.e. attacks of severe hypertension and tachycardia, marked blood pressure fluctuation, and a high plasma concentration of norepinephrine [3,4]. Also, they pointed out the possibility that the sympathetic hyperactivity can cause circulatory collapse or sudden death in respirator-dependent ALS. Although the pathophysiology of sympathetic hyperactivity has not been fully elucidated in ALS patients, the involvement of the central autonomic network is speculated. In some cases of SMA type 1, lesions in the posteroventral thalamic nuclei, Clarke’s column and spinal ganglion have been pathologically verified [2]. In case 3, we previously reported neuroradiological and neurophysiological changes in the thalamus, i.e. high signal intensity in T2-weighted images on brain magnetic resonance imaging and altered spindles on electoroencephalography, although she
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exhibited no sensory disturbances and SSEP were not examined [5]. Several nuclei of the thalamus are known to interconnect with other brain regions and to thereby control autonomic functions [15]. The presence of a latent thalamic lesion may suggest the possibility of involvement of the central autonomic network in SMA type 1 like in ALS. A latent thalamic lesion is also possible in case 1 showing the lack of thalamic components of SSEP, although MRI failed to detect any thalamic changes. Since sustained mechanical ventilation support for SMA type 1 patients has long been practiced in Japan [16] and autonomic disturbances seem to occur more frequently than previously considered, we believe that the detailed analysis of autonomic functions is a prerequisite for improving the quality of life of longsurviving SMA type 1 patients.
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