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Autonomic nervous system abnormalities in spinocerebellar ataxia type 2: A cardiovascular neurophysiologic study
Journal of the Neurological Sciences 275 (2008) 60–63
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Autonomic nervous system abnormalities in spinocerebellar ataxia type 2: A cardiovascular neurophysiologic study G. De Joanna a, A. De Rosa b,⁎, E. Salvatore b, I. Castaldo c, N. De Luca d, R. Izzo d, V. Manzo a, A. Filla b, G. De Michele b a
Department of Neurological Sciences, A.O.R.N. “A. Cardarelli”, via Cardarelli 9, 80131, Naples, Italy Department of Neurological Sciences, Federico II University, via Pansini 5, 80131, Naples, Italy Department of Cellular and Molecular Biology and Pathology, Federico II University, IEOS CNR, Naples, Italy d Department of Internal Medicine, Cardiovascular and Immunological Pathology, Federico II University, Naples, Italy b c
a r t i c l e
i n f o
Article history: Received 25 March 2008 Received in revised form 6 June 2008 Accepted 17 July 2008 Available online 27 August 2008 Keywords: Spinocerebellar ataxia SCA2 Autonomic nervous system Dysautonomia Cardiovascular system Neurophysiologic study
a b s t r a c t Autonomic nervous system dysfunction is part of the spinocerebellar ataxia (SCA) clinical picture, but few data are available on this topic. The present study is aimed to report a detailed investigation of autonomic nervous system in patients with molecular diagnosis of SCA type 2, one of the most frequent forms and the commonest in Italy. Nine patients with a mild to moderate form of SCA2 underwent a questionnaire about dysautonomic symptoms and a complete cardiovascular neurophysiologic evaluation of both sympathetic and parasympathetic system, comprising head-up tilt, standing, isometric hand grip, cold pressure, mental arithmetic, Valsalva manoeuvre, deep breathing, and hyperventilation tests. An echocardiographic study and Holter-ECG recording were also performed. All patients complained dysautonomic problems regarding urinary tract, cardiovascular system, or gastrointestinal dysfunction. The neurophysiologic study showed both sympathetic and parasympathetic involvement, with highly variable degree and pattern of dysautonomia. The present study results show that the autonomic dysfunction is common in SCA2 representing a significant component of the complex picture of the disease. We found a wide spectrum of cardiovascular autonomic abnormalities, without a typical pattern of dysfunction and without correlation with clinical variables. © 2008 Elsevier B.V. All rights reserved.
1. Introduction Autosomal dominant cerebellar ataxias are heterogeneous neurodegenerative disorders, whose pathological features are degeneration of cerebellum and, in most cases, of basal ganglia, brainstem, spinal cord, and peripheral nerves [1]. To date molecular genetics showed genetic heterogeneity and almost thirty loci have been identified. An abnormally expanded cytosine-adenine-guanine (CAG) triplet sequence in the coding sequence of the gene is the underlying mutation in most SCAs. Spinocerebellar ataxia type 2 (SCA2) is one of the most frequent form and the commonest in Italy [2]. The SCA2 gene has been mapped to chromosome 12q23-24 and codes for ataxin-2, a protein of unknown function [3]. The clinical features of SCA2 are gait and limb ataxia, dysarthria, supranuclear ophthalmoplegia with early decrease in saccade velocity, peripheral neuropathy, cramps, amyo-
⁎ Corresponding author. Dipartimento di Scienze Neurologiche, Università degli Studi di Napoli Federico II, Via Pansini 5, I-80131, Napoli, Italy. Tel.: +39 081 7463711; fax: +39 081 5469861. E-mail address: [email protected] (A. De Rosa). 0022-510X/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2008.07.015
trophy, reduced vibration sense, dementia, and extrapyramidal features [1,4]. Few data are available on autonomic nervous system (ANS) dysfunction in SCAs. To date a clinical study on SCA2 patients [5] and a neurophysiologic study on SCA3 patients [6] have been performed, the latter showing both sympathetic and parasympathetic dysfunction. The aim of the present study is to assess the autonomic nervous system function in SCA2 patients through a structured interview and a complete battery of cardiovascular autonomic tests. 2. Patients and methods 2.1. Patients Nine patients (six men, three women) with molecular diagnosis of SCA2 from eight unrelated families were included in the study (Table 1). Patients 1 and 2 were father and son. We recruited only patients which were ambulant, cooperative and without cognitive impairment. We excluded patients with known cardiovascular or metabolic diseases, or in treatment with drugs interfering with autonomic functions, such as tranquillants, antidepressants, neuroleptics, α-adrenoceptor blockers, beta blockers, anticholinergic agents, antihypertensives, and antiarrhythmics.
G. De Joanna et al. / Journal of the Neurological Sciences 275 (2008) 60–63
underwent echocardiography and seven of them Holter-ECG recording [8]. Brain MRI was performed in all cases.
Table 1 Demographic, clinical, and genetic features
Sex Age Onset DD FS ICARS CAG MRI EchoCG HolterECG AuSco
Pt1
Pt2
Pt3
Pt4
Pt5
Pt6
Pt7
Pt8
Pt9
M 47 38 9 2 25 22–38 PCA N NP
M 19 17 2 2 26 27–50 PCA + CS N NP
M 47 29 18 2 16 22–39 PCA N N
M 49 37 12 3 40 22–38 PCA N N
M 51 33 18 2 25 22–39 PCA N N
M 40 30 10 2 22 22–38 PCA N N
F 33 24 9 2 32 22–42 PCA+CS N N
F 34 26 8 3 24 22–40 PCA N N
F 55 40 15 2 40 23–44 PCA + CS N N
5
1
5
7
5
4
4
7
0
DD = disease duration; FS = functional scale [6]; ICARS = International Cooperative Ataxia Rating Scale [7]; CAG: cytosine-adenine-guanine repeat sizes on the two alleles; PCA = pontocerebellar atrophy; CS = hot cross bun sign; AuSco: autonomic score; N = Normal; NP = not performed.
Mean disease onset±SD was 30.4±7.4 years (range 17–40) and mean age at examination 41.6±11.3 years (19–55). Mean disease duration was 11.2± 5.2 years (2–18). Mean CAG expansion was 40.5±4.4 triplets (38–50). The clinical picture severity was evaluated by the International Cooperative Ataxia Rating Scale (ICARS) [7], (0=normal, 100=maximal severity), and the disease stage was evaluated by a functional scale (FS) [6]: stage 1, patient with minimal signs and independent walking; stage 2, mild symptoms and occasional assistance for walking; stage 3, completely developed symptoms and needed support for walking; stage 4, patient confined to wheelchair; stage 5, the patient is bedridden. All patients
Table 2 Questionnaire for autonomic nervous system function Symptoms relating to postural hypotension Dizziness Loss of consciousness Visual disturbances on standing/exercise Coathanger pain on standing/exercise Fatigue on modest standing/exercise Worse in the morning Worse after meals Worse in hot environment Worse with a hot bath/shower Gastrointestinal function Gastroesophageal reflux Constipation Diarrhea Alternating constipation/diarrhea Incontinence Bladder function Frequency Urgency Incontinence Nocturia Hesitancy/weak urine stream Retention Sexual function Erectile failure Nocturnal erection loss Ejaculatory failure Sweating Increased Decreased Salivation Drooling Dry mouth Lacrimation Tearing Dry eyes
61
2.2. Autonomic tests Patients were administered a structured questionnaire about autonomic symptoms in the following domains: postural hypotension, gastrointestinal function, bladder and erectile function, sweating, salivation, and lacrimation (Table 2). All patients underwent a complete battery of cardiovascular autonomic reflexes tests. Autonomic testing was performed according to standard clinical methods [9,10]. Caffeine-containing beverages, cigarettes, and alcohol were not allowed for at least 24 h before testing. No patient was taking drugs that could modify autonomic responses. All tests were conducted in the morning, at least 2 h after a light breakfast, in a quiet and temperature-controlled (21–24 °C) laboratory. Patients were lying supine on the horizontal electrical tilt table and advised to be relaxed and remain silent during the whole examination time. A finger cuff of an infrared photoplethysmograph sensor for heart rate (Nellcor pulse oximeter, OXIMAX, N-595, Pleasanton, Ca, USA) was placed on the third finger of the right hand to provide non-invasive continuous beat-to-beat finger heart rate measurement and recording. Blood pressure was monitored by a digital automatic sphygmomanometer (Moretti smart-inflate, DM 407, San Giovanni Valdarno (AR), Italy). Cardiac activity was monitored by an automatic, digital electrocardiograph (EPG Junior, FIAB, Vicchio (FI), Italy). Basal measurements were performed while the subject was in the supine position for at least 15 min, in order to stabilize blood pressure (BP) and heart rate (HR). Each patient underwent a standard battery comprising eight noninvasive tests [9]. Head-up tilt: The patient was tilted 60° upright and BP and HR were continuously measured in this position for 9 min. Cold pressure test: Ice packs were placed over and under the patient's hand and forearm for 90 s. BP and a HR were recorded during the last 30 s. Isometric hand grip: Patient was asked to squeeze maximally a cloth sphygmomanometer cuff, and afterward to squeeze at 1/3 maximum power for 3 min. BP and HR were recorded during the last 30 s of isometric exercise. Valsalva manoeuvre: The patient was asked to inspire deeply, then a mouthpiece was placed in the patient's mouth and the patient was asked to expire forcefully through, so as to raise the mercury column to 40 mm Hg. The pressure was maintained at 40 mm Hg for 15 s followed by normal breathing. The Valsalva ratio (the ratio of the maximal HR in phase II to the minimal HR in phase IV) and the presence of BP overshoot (the rising of BP over the baseline value) during the IV phase were recorded. Hyperventilation: Patient was asked to hyperventilate for 1 min and HR was recorded during the last 30 s. Mental arithmetic: The patient was asked to subtract 7 or 17 from a suitable starting number (e.g., 100 or 400), depending on the patient's level of education. BP and HR were measured after a period of 2 min. Deep breathing: Patient was asked to breathe deeply at six breaths per minute for 1 min and the difference between the maximum and minimum HR was estimated. Standing: The patient was asked to stand for up to 5 min and BP and HR were recorded after
Table 3 Results of the autonomic nervous system function questionnaire Pt1 Pt2 Pt3 Pt4 Pt5 Pt6 Pt7 Pt8 Pt9 Total abnormal Postural hypotension Gastrointestinal function Bladder function Sexual function Sweating Salivation Eyes Total abnormal
A P
P P
P P
P P
P A
P P
P P
P A
P P
8 7
P A A P A 3
P A A A P 4
P A P A P 5
P P A P A 5
P A A P A 3
P P P A P 6
P – A A A 3
P – A A A 2
P – A P A 4
9 2 2 4 3
P = symptoms present; A = absent.
62
G. De Joanna et al. / Journal of the Neurological Sciences 275 (2008) 60–63
2 and 5 min. In between each test, the patient was allowed to rest till BP and HR achieved baseline values. The test results were compared with normal subjects values [9] and considered abnormal when outside the 95% confidence intervals of their age decade. To summarize the results of autonomic tests an overall autonomic score (AuSco) was calculated by adding 1 for each abnormal test (Table 1). Correlation between autonomic symptoms (number of abnormal systems at the questionnaire, see Table 3), electrophysiological tests (AuSco), and clinical data (disease severity and duration, age at onset, and number of CAG repeats) were investigated by the Pearson correlation coefficient. CAG repeats of SCA2 were analyzed on genomic DNA by polymerase chain reaction using SCA2A–SCA2B as oligonucleotide primers to amplify the surrounding region. Amplified products were separated in 6% polyacrilamide gel and analyzed by silver staining [4]. 3. Results All patients were ambulant at the time of the study, and only two of them required a support for walking (Table 1). Mean ICARS score was 27.7 ± 8.1 (range 16–40). Echocardiography and Holter-ECG recording resulted normal in all patients. MRI brain showed brainstem and cerebellar atrophy in all patients, and hot cross bun sign in three of them. The results of the autonomic questionnaire are summarized in Table 3. Eight patients complained of symptoms related to postural hypotension, mostly dizziness, heat intolerance, and post-prandial somnolence. Gastrointestinal symptoms were present in seven patients; in particular gastroesophageal reflux was complained by six. All patients complained of urinary tract dysfunction, the most common symptoms being urgency, nocturia, incontinence, and weak urine stream. Two of six men had impotentia erigendi. Hyperhidrosis was present in two, dry mouth in three, sialorrhea in one, increased lacrimation in one, and dry eyes in one. The results of cardiovascular autonomic tests are summarized in Table 4. The Head-up tilt test was altered in six patients (67%). Postural tachycardia was present in three (patients 1, 5, and 6); patient 4 showed marked bradycardia at 2 min. Patient 7 showed no HR and BP response. Systolic and diastolic BP fell at 2 min in patient 8, but recovered at 5 min. Standing test was pathologic in five patients (56%). Two (patients 5 and 6) showed exaggerated increase of HR; patient 4 had postural tachycardia (increase of 86 bpm) at 2 min, associated with systolic and diastolic BP fall and all these abnormalities recovered at 5 min. Diastolic BP decreased in patient 1. The last patient (patient 8) had a symptomatic fall of both BP and HR. Gripping isometric exercise was altered in eight patients (89%). Abnormal HR and BP increase after 3 min of isometric exercise was observed in five (patients 1, 2, 3, 6, and 7). The HR increase was striking, with a maximal rise of 80 bpm in patient 1. On the other hand, we observed a systolic and diastolic BP fall in patient 5, associated with exaggerated tachycardia, and in patient 4, associated with
Table 4 Results of the autonomic cardiovascular tests Pt1 Pt2 Pt3 Pt4 Pt5 Pt6 Pt7 Pt8 Pt9 Total abnormal 60° head-up tilt Standing Hand gripping Cold Arithmetic Valsalva manoeuvre Deep breathing Hyperventilation
A A A N N N A A
N = Normal; A = Abnormal.
N N A N N N N N
N N A A A A A N
A A A N A A A A
A A A A A N N N
A A A A N N N N
A N A A N N N A
A A A A A A A N
N N N N N N N N
6 5 8 5 4 3 4 3
bradycardia. Patient 8 showed dramatic bradycardia (decrease of 34 bpm). Cold pressure test was pathologic in five patients (56%), with absent response in patients 3, 6, 7, and 8 and paradoxical BP fall in patient 5 (systolic: −43 mm Hg; diastolic: −33 mm Hg) . Arithmetic test was altered in four patients (44%), with exaggerated BP increase in patient 8, and no BP increase in three (patients 3, 4, and 5), associated with bradycardia in patient 4. Valsalva manoeuvre was abnormal in three patients (33%) with low Valsalva ratio and poor HR variability. The alteration was mild in patient 4 and marked in patients 3 and 8. Deep breathing test was mildly abnormal in four patients (44%), with abnormal HR increase in one (patient 1) and reduced increase in three (patients 3, 4, and 8). Hyperventilation test was abnormal in three patients (33%), showing exaggerated HR increase. We observed no correlations between autonomic symptoms, electrophysiological tests, and clinical data. 4. Discussion To date few data are available about ANS dysfunction in SCAs. A clinical study, performed on 21 Cuban SCA2 patients in an advanced disease stage, showed constant signs of dysautonomia, the most frequent features being orthostatic hypotension (95%), constipation (90%), distal coldness (57%), urinary incontinence (52%), and increased lacrimation (52%) [5]. Dysautonomic features (dysuria, constipation, and sexual dysfunction) have been described in a patient affected with SCA17, mimicking the cerebellar form of multiple system atrophy [11]. 123 I-MIBG myocardial uptake scintigraphy and sympathetic skin response have been investigated in 19 SCA3 patients, showing cardiac and sudomotor sympathetic dysfunction [12]. Another study assessed autonomic function in 15 SCA3 patients, using a questionnaire and two electrophysiological tests [6]. The most frequent reported abnormalities were nocturia, cold intolerance, and orthostatic dizziness, present in about half of patients. Prolonged latency or absence of sympathetic skin response to electrical stimulation and abnormal R–R interval variation were identified in more than 70% of the patients. The present study is the first neurophysiologic evaluation of ANS in patients with SCA2 through a complete battery of cardiovascular autonomic reflexes tests. Among them, head-up tilt, standing, and Valsalva manoeuvre are aimed to explore the integrity of the baroreflex arc, the last test mainly, but not exclusively, investigating the vagal component; gripping isometric exercise, cold pressure and arithmetic tests evaluate efferent sympathetic pathways; deep breathing and hyperventilation tests are useful to assess HR vagal control. We selected patients with mild to moderate disability to obtain full cooperation in performing the tests and to avoid secondary autonomic dysfunction due to prolonged lying position. Autonomic symptoms, investigated by a questionnaire, were common in our patients. All complained of urinary tract dysfunction, eight reported postural hypotension symptoms and seven gastrointestinal symptoms. Bladder and sexual dysfunction significantly contribute to the patients' disability. The cardiovascular neurophysiologic evaluation showed a high range variability of responses, with different degrees and combinations of autonomic abnormalities, in the absence of a typical pattern of dysfunction (Table 4). One patient (patient 9) had entirely normal tests. An initial ANS impairment was observed in patients 1, 2, 5, and 6, with exaggerated HR increase at some tests, but substantial preservation of the arterial baroreflex pathways. Finally, the abnormalities found in patients 3, 4, 7, and 8 are consistent with a prominent ANS failure with baroreflex arc dysfunction. Although a SCA2 specific pattern of ANS dysfunction did not stand out in our patients, a marked chronotropic cardiac response was often observed, in particular in the tilt, standing, hand gripping and
G. De Joanna et al. / Journal of the Neurological Sciences 275 (2008) 60–63
hyperventilation tests. Increased tachycardia, which sometimes was above 110 bpm, may be related to an increased sympathetic outflow, rather than to a simple withdrawal of vagal tone. Since hypovolaemia, cardiomyopathy, and other non-neurogenic cause of ineffective BP control can be excluded in our patients, this amplified sympathetic response may be interpreted as compensatory to an initial autonomic impairment. A somewhat surprising result is the absence of correlation between ANS dysfunction in our patients and either molecular or clinical findings. Of course, the small number of patients and their relative homogeneity for clinical severity and expansion size could have prevented from observing significant correlations. Another possible explanation is that the progression of ANS dysfunction does not parallel the neurodegeneration processes which cause the motor defects. It is interesting to note that a correlation between clinical features and autonomic involvement was not evident in a patho-anathomical study in six SCA2 patients [13]. This study also showed complete sparing of the autonomic nuclei in the patient with the latest onset (55 years). Similarly, we observed normal neurophysiologic evaluation in patient 9, the individual with the latest onset in our series. The main cerebral areas involved in autonomic system regulation are the hypothalamus and a few nuclei of brainstem, such as the locus coeruleus (LC), the nucleus tractus solitarius (NTS), the nucleus ambiguus (NA), the dorsal motor nucleus of the vagus (DMV), the rostral ventrolateral medulla (RVLM) neurons, the pontine micturition center (Barrington's nucleus, PMC), and the reticular paramedian nucleus (RPN). The NTS is a key component of the central pathway for cardiovascular regulation, acting as a terminal for primary baroreceptor afferents. The sympathetic output to the heart is through the RPN, whereas the ventrolateral portion of NA provides most of the vagal output, with less contributions from DMV, which is considered to be mainly responsible for gastrointestinal motility. RVLM projects to sympathetic preganglionic neurones and is critical for the tonic and reflex control of arterial pressure. PMC projects to both the LC and preganglionic column of the lumbosacral spinal cord, coordinating brain noradrenergic activity with pelvic visceral functions. LC has a role in bladder and cardiovascular control, in particular in the arousal caused by bladder distension. Pathological studies on SCA2 are rare and often omit examination of the autonomic nuclei. Little neuronal loss has been reported in the LC of seven patients from the Cuban cluster of families, which later has been shown to be affected with SCA2 [14]. A more recent study investigated some brainstem autonomic nuclei in patients with SCA2, demonstrating moderate to severe cell loss and astrogliosis of NTS, NA, and DMV in five of six patients [13]. Atrophy and demyelination of autonomic fiber tracts were also found. The prominent involvement of NTS, NA, and DMV may be related to cardiovagal failure and abnormal gastrointestinal motility of SCA2 patients.
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As far as we know, degeneration of PMC and other pontine structures regulating bladder voiding has not been investigated in SCA2, however, as suggested by constant pons atrophy at MRI, their involvement is likely. The inhibitory input loss of the PMC could explain a detrusoral hyperreflessia causing urgency and incontinence. Although the degeneration of brainstem autonomic nuclei may well explain dysautonomia in SCA2, the almost constant sensorymotor axonal neuropathy described in these patients also may play an important role in the autonomic dysfunction of SCA2 patients. Skin biopsies to examine autonomic cutaneous nerve fibers, small fiber electrophysiological studies, and 123I-MIBG myocardial uptake scintigraphic examinations should be performed in these patients to correlate the results with the autonomic abnormalities. References [1] Schols L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 2004;3: 291–304. [2] Filla A, Mariotti C, Caruso G, Coppola G, Cocozza S, Castaldo I, et al. Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families. Eur Neurol 2000;44:31–6. [3] Pulst SM, Nechiporuk T, Nechiporuk A, Gispert S, Chen XN, Lopes-Cendes I, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 1996;4:269–76. [4] Filla A, De Michele G, Santoro L, Calabrese O, Castaldo I, Giuffrida S, et al. Spinocerebellar ataxia type 2 in southern Italy: a clinical and molecular study of 30 families. J Neurol 1999;246:467–71. [5] Sanchez-Cruz G, Velazquez-Perez L, Gomez-Pena L, Martinez-Gongora E, Castellano-Sanchez G, Santos-Falcon N. Dysautonomic features in patients with Cuban type 2 spinocerebellar ataxia. Rev Neurol 2001;33:428–34. [6] Yeh TH, Lu CS, Chou YH, Chong CC, Wu T, Han NH, et al. Autonomic dysfunction in Machado–Joseph disease. Arch Neurol 2005;62:630–6. [7] Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci 1997;145:205–11. [8] Petretta M, Marciano F, Bianchi V, Migaux ML, Valva G, De Luca N, et al. Power spectral analysis of heart period variability in hypertensive patients with left ventricular hypertrophy. Am J Hypertens 1995;8:1206–13. [9] Mathias CJ, Bannister R. Investigations of autonomic disorders. In: Bannister R, Mathias CJ, editors. Autonomic Failure. Oxford: Oxford University Press; 1999. p. 169–95. [10] Del Sorbo F, Elia AE, De Joanna G, Romito LM, Garavaglia B, Albanese A. Normal cardiovascular reflex testing in patients with parkin disease. Mov Disord 2007;22: 528–32. [11] Lin IS, Wu RM, Lee-Chen GJ, Shan DE, Gwinn-Hardy K. The SCA17 phenotype can include features of MSA-C, PSP and cognitive impairment. Parkinsonism Relat Disord 2007;13:246–9. [12] Kazuta T, Hayashi M, Shimizu T, Iwasaki A, Nakamura S, Hirai S. Autonomic dysfunction in Machado–Joseph disease assessed by iodine123-labeled metaiodobenzylguanidine myocardial scintigraphy. Clinic Auton Res 2000;10:111–5. [13] Gierga K, Burk K, Bauer M, Orozco Diaz G, Auburger G, Schultz C, et al. Involvement of the cranial nerves and their nuclei in spinocerebellar ataxia type 2 (SCA2). Acta Neuropathol (Berl) 2005;109:617–31. [14] Orozco G, Estrada R, Perry TL, Araña J, Fernandez R, Gonzalez-Quevedo A, et al. Dominantly inherited olivopontocerebellar atrophy from eastern Cuba. Clinical, neuropathological, and biochemical findings. J Neurol Sci 1989;93:37–50.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Autonomic nervous system abnormalities in spinocerebellar ataxia type 2: A cardiovascular neurophysiologic study G. De Joanna a, A. De Rosa b,⁎, E. Salvatore b, I. Castaldo c, N. De Luca d, R. Izzo d, V. Manzo a, A. Filla b, G. De Michele b a
Department of Neurological Sciences, A.O.R.N. “A. Cardarelli”, via Cardarelli 9, 80131, Naples, Italy Department of Neurological Sciences, Federico II University, via Pansini 5, 80131, Naples, Italy Department of Cellular and Molecular Biology and Pathology, Federico II University, IEOS CNR, Naples, Italy d Department of Internal Medicine, Cardiovascular and Immunological Pathology, Federico II University, Naples, Italy b c
a r t i c l e
i n f o
Article history: Received 25 March 2008 Received in revised form 6 June 2008 Accepted 17 July 2008 Available online 27 August 2008 Keywords: Spinocerebellar ataxia SCA2 Autonomic nervous system Dysautonomia Cardiovascular system Neurophysiologic study
a b s t r a c t Autonomic nervous system dysfunction is part of the spinocerebellar ataxia (SCA) clinical picture, but few data are available on this topic. The present study is aimed to report a detailed investigation of autonomic nervous system in patients with molecular diagnosis of SCA type 2, one of the most frequent forms and the commonest in Italy. Nine patients with a mild to moderate form of SCA2 underwent a questionnaire about dysautonomic symptoms and a complete cardiovascular neurophysiologic evaluation of both sympathetic and parasympathetic system, comprising head-up tilt, standing, isometric hand grip, cold pressure, mental arithmetic, Valsalva manoeuvre, deep breathing, and hyperventilation tests. An echocardiographic study and Holter-ECG recording were also performed. All patients complained dysautonomic problems regarding urinary tract, cardiovascular system, or gastrointestinal dysfunction. The neurophysiologic study showed both sympathetic and parasympathetic involvement, with highly variable degree and pattern of dysautonomia. The present study results show that the autonomic dysfunction is common in SCA2 representing a significant component of the complex picture of the disease. We found a wide spectrum of cardiovascular autonomic abnormalities, without a typical pattern of dysfunction and without correlation with clinical variables. © 2008 Elsevier B.V. All rights reserved.
1. Introduction Autosomal dominant cerebellar ataxias are heterogeneous neurodegenerative disorders, whose pathological features are degeneration of cerebellum and, in most cases, of basal ganglia, brainstem, spinal cord, and peripheral nerves [1]. To date molecular genetics showed genetic heterogeneity and almost thirty loci have been identified. An abnormally expanded cytosine-adenine-guanine (CAG) triplet sequence in the coding sequence of the gene is the underlying mutation in most SCAs. Spinocerebellar ataxia type 2 (SCA2) is one of the most frequent form and the commonest in Italy [2]. The SCA2 gene has been mapped to chromosome 12q23-24 and codes for ataxin-2, a protein of unknown function [3]. The clinical features of SCA2 are gait and limb ataxia, dysarthria, supranuclear ophthalmoplegia with early decrease in saccade velocity, peripheral neuropathy, cramps, amyo-
⁎ Corresponding author. Dipartimento di Scienze Neurologiche, Università degli Studi di Napoli Federico II, Via Pansini 5, I-80131, Napoli, Italy. Tel.: +39 081 7463711; fax: +39 081 5469861. E-mail address: [email protected] (A. De Rosa). 0022-510X/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2008.07.015
trophy, reduced vibration sense, dementia, and extrapyramidal features [1,4]. Few data are available on autonomic nervous system (ANS) dysfunction in SCAs. To date a clinical study on SCA2 patients [5] and a neurophysiologic study on SCA3 patients [6] have been performed, the latter showing both sympathetic and parasympathetic dysfunction. The aim of the present study is to assess the autonomic nervous system function in SCA2 patients through a structured interview and a complete battery of cardiovascular autonomic tests. 2. Patients and methods 2.1. Patients Nine patients (six men, three women) with molecular diagnosis of SCA2 from eight unrelated families were included in the study (Table 1). Patients 1 and 2 were father and son. We recruited only patients which were ambulant, cooperative and without cognitive impairment. We excluded patients with known cardiovascular or metabolic diseases, or in treatment with drugs interfering with autonomic functions, such as tranquillants, antidepressants, neuroleptics, α-adrenoceptor blockers, beta blockers, anticholinergic agents, antihypertensives, and antiarrhythmics.
G. De Joanna et al. / Journal of the Neurological Sciences 275 (2008) 60–63
underwent echocardiography and seven of them Holter-ECG recording [8]. Brain MRI was performed in all cases.
Table 1 Demographic, clinical, and genetic features
Sex Age Onset DD FS ICARS CAG MRI EchoCG HolterECG AuSco
Pt1
Pt2
Pt3
Pt4
Pt5
Pt6
Pt7
Pt8
Pt9
M 47 38 9 2 25 22–38 PCA N NP
M 19 17 2 2 26 27–50 PCA + CS N NP
M 47 29 18 2 16 22–39 PCA N N
M 49 37 12 3 40 22–38 PCA N N
M 51 33 18 2 25 22–39 PCA N N
M 40 30 10 2 22 22–38 PCA N N
F 33 24 9 2 32 22–42 PCA+CS N N
F 34 26 8 3 24 22–40 PCA N N
F 55 40 15 2 40 23–44 PCA + CS N N
5
1
5
7
5
4
4
7
0
DD = disease duration; FS = functional scale [6]; ICARS = International Cooperative Ataxia Rating Scale [7]; CAG: cytosine-adenine-guanine repeat sizes on the two alleles; PCA = pontocerebellar atrophy; CS = hot cross bun sign; AuSco: autonomic score; N = Normal; NP = not performed.
Mean disease onset±SD was 30.4±7.4 years (range 17–40) and mean age at examination 41.6±11.3 years (19–55). Mean disease duration was 11.2± 5.2 years (2–18). Mean CAG expansion was 40.5±4.4 triplets (38–50). The clinical picture severity was evaluated by the International Cooperative Ataxia Rating Scale (ICARS) [7], (0=normal, 100=maximal severity), and the disease stage was evaluated by a functional scale (FS) [6]: stage 1, patient with minimal signs and independent walking; stage 2, mild symptoms and occasional assistance for walking; stage 3, completely developed symptoms and needed support for walking; stage 4, patient confined to wheelchair; stage 5, the patient is bedridden. All patients
Table 2 Questionnaire for autonomic nervous system function Symptoms relating to postural hypotension Dizziness Loss of consciousness Visual disturbances on standing/exercise Coathanger pain on standing/exercise Fatigue on modest standing/exercise Worse in the morning Worse after meals Worse in hot environment Worse with a hot bath/shower Gastrointestinal function Gastroesophageal reflux Constipation Diarrhea Alternating constipation/diarrhea Incontinence Bladder function Frequency Urgency Incontinence Nocturia Hesitancy/weak urine stream Retention Sexual function Erectile failure Nocturnal erection loss Ejaculatory failure Sweating Increased Decreased Salivation Drooling Dry mouth Lacrimation Tearing Dry eyes
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2.2. Autonomic tests Patients were administered a structured questionnaire about autonomic symptoms in the following domains: postural hypotension, gastrointestinal function, bladder and erectile function, sweating, salivation, and lacrimation (Table 2). All patients underwent a complete battery of cardiovascular autonomic reflexes tests. Autonomic testing was performed according to standard clinical methods [9,10]. Caffeine-containing beverages, cigarettes, and alcohol were not allowed for at least 24 h before testing. No patient was taking drugs that could modify autonomic responses. All tests were conducted in the morning, at least 2 h after a light breakfast, in a quiet and temperature-controlled (21–24 °C) laboratory. Patients were lying supine on the horizontal electrical tilt table and advised to be relaxed and remain silent during the whole examination time. A finger cuff of an infrared photoplethysmograph sensor for heart rate (Nellcor pulse oximeter, OXIMAX, N-595, Pleasanton, Ca, USA) was placed on the third finger of the right hand to provide non-invasive continuous beat-to-beat finger heart rate measurement and recording. Blood pressure was monitored by a digital automatic sphygmomanometer (Moretti smart-inflate, DM 407, San Giovanni Valdarno (AR), Italy). Cardiac activity was monitored by an automatic, digital electrocardiograph (EPG Junior, FIAB, Vicchio (FI), Italy). Basal measurements were performed while the subject was in the supine position for at least 15 min, in order to stabilize blood pressure (BP) and heart rate (HR). Each patient underwent a standard battery comprising eight noninvasive tests [9]. Head-up tilt: The patient was tilted 60° upright and BP and HR were continuously measured in this position for 9 min. Cold pressure test: Ice packs were placed over and under the patient's hand and forearm for 90 s. BP and a HR were recorded during the last 30 s. Isometric hand grip: Patient was asked to squeeze maximally a cloth sphygmomanometer cuff, and afterward to squeeze at 1/3 maximum power for 3 min. BP and HR were recorded during the last 30 s of isometric exercise. Valsalva manoeuvre: The patient was asked to inspire deeply, then a mouthpiece was placed in the patient's mouth and the patient was asked to expire forcefully through, so as to raise the mercury column to 40 mm Hg. The pressure was maintained at 40 mm Hg for 15 s followed by normal breathing. The Valsalva ratio (the ratio of the maximal HR in phase II to the minimal HR in phase IV) and the presence of BP overshoot (the rising of BP over the baseline value) during the IV phase were recorded. Hyperventilation: Patient was asked to hyperventilate for 1 min and HR was recorded during the last 30 s. Mental arithmetic: The patient was asked to subtract 7 or 17 from a suitable starting number (e.g., 100 or 400), depending on the patient's level of education. BP and HR were measured after a period of 2 min. Deep breathing: Patient was asked to breathe deeply at six breaths per minute for 1 min and the difference between the maximum and minimum HR was estimated. Standing: The patient was asked to stand for up to 5 min and BP and HR were recorded after
Table 3 Results of the autonomic nervous system function questionnaire Pt1 Pt2 Pt3 Pt4 Pt5 Pt6 Pt7 Pt8 Pt9 Total abnormal Postural hypotension Gastrointestinal function Bladder function Sexual function Sweating Salivation Eyes Total abnormal
A P
P P
P P
P P
P A
P P
P P
P A
P P
8 7
P A A P A 3
P A A A P 4
P A P A P 5
P P A P A 5
P A A P A 3
P P P A P 6
P – A A A 3
P – A A A 2
P – A P A 4
9 2 2 4 3
P = symptoms present; A = absent.
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2 and 5 min. In between each test, the patient was allowed to rest till BP and HR achieved baseline values. The test results were compared with normal subjects values [9] and considered abnormal when outside the 95% confidence intervals of their age decade. To summarize the results of autonomic tests an overall autonomic score (AuSco) was calculated by adding 1 for each abnormal test (Table 1). Correlation between autonomic symptoms (number of abnormal systems at the questionnaire, see Table 3), electrophysiological tests (AuSco), and clinical data (disease severity and duration, age at onset, and number of CAG repeats) were investigated by the Pearson correlation coefficient. CAG repeats of SCA2 were analyzed on genomic DNA by polymerase chain reaction using SCA2A–SCA2B as oligonucleotide primers to amplify the surrounding region. Amplified products were separated in 6% polyacrilamide gel and analyzed by silver staining [4]. 3. Results All patients were ambulant at the time of the study, and only two of them required a support for walking (Table 1). Mean ICARS score was 27.7 ± 8.1 (range 16–40). Echocardiography and Holter-ECG recording resulted normal in all patients. MRI brain showed brainstem and cerebellar atrophy in all patients, and hot cross bun sign in three of them. The results of the autonomic questionnaire are summarized in Table 3. Eight patients complained of symptoms related to postural hypotension, mostly dizziness, heat intolerance, and post-prandial somnolence. Gastrointestinal symptoms were present in seven patients; in particular gastroesophageal reflux was complained by six. All patients complained of urinary tract dysfunction, the most common symptoms being urgency, nocturia, incontinence, and weak urine stream. Two of six men had impotentia erigendi. Hyperhidrosis was present in two, dry mouth in three, sialorrhea in one, increased lacrimation in one, and dry eyes in one. The results of cardiovascular autonomic tests are summarized in Table 4. The Head-up tilt test was altered in six patients (67%). Postural tachycardia was present in three (patients 1, 5, and 6); patient 4 showed marked bradycardia at 2 min. Patient 7 showed no HR and BP response. Systolic and diastolic BP fell at 2 min in patient 8, but recovered at 5 min. Standing test was pathologic in five patients (56%). Two (patients 5 and 6) showed exaggerated increase of HR; patient 4 had postural tachycardia (increase of 86 bpm) at 2 min, associated with systolic and diastolic BP fall and all these abnormalities recovered at 5 min. Diastolic BP decreased in patient 1. The last patient (patient 8) had a symptomatic fall of both BP and HR. Gripping isometric exercise was altered in eight patients (89%). Abnormal HR and BP increase after 3 min of isometric exercise was observed in five (patients 1, 2, 3, 6, and 7). The HR increase was striking, with a maximal rise of 80 bpm in patient 1. On the other hand, we observed a systolic and diastolic BP fall in patient 5, associated with exaggerated tachycardia, and in patient 4, associated with
Table 4 Results of the autonomic cardiovascular tests Pt1 Pt2 Pt3 Pt4 Pt5 Pt6 Pt7 Pt8 Pt9 Total abnormal 60° head-up tilt Standing Hand gripping Cold Arithmetic Valsalva manoeuvre Deep breathing Hyperventilation
A A A N N N A A
N = Normal; A = Abnormal.
N N A N N N N N
N N A A A A A N
A A A N A A A A
A A A A A N N N
A A A A N N N N
A N A A N N N A
A A A A A A A N
N N N N N N N N
6 5 8 5 4 3 4 3
bradycardia. Patient 8 showed dramatic bradycardia (decrease of 34 bpm). Cold pressure test was pathologic in five patients (56%), with absent response in patients 3, 6, 7, and 8 and paradoxical BP fall in patient 5 (systolic: −43 mm Hg; diastolic: −33 mm Hg) . Arithmetic test was altered in four patients (44%), with exaggerated BP increase in patient 8, and no BP increase in three (patients 3, 4, and 5), associated with bradycardia in patient 4. Valsalva manoeuvre was abnormal in three patients (33%) with low Valsalva ratio and poor HR variability. The alteration was mild in patient 4 and marked in patients 3 and 8. Deep breathing test was mildly abnormal in four patients (44%), with abnormal HR increase in one (patient 1) and reduced increase in three (patients 3, 4, and 8). Hyperventilation test was abnormal in three patients (33%), showing exaggerated HR increase. We observed no correlations between autonomic symptoms, electrophysiological tests, and clinical data. 4. Discussion To date few data are available about ANS dysfunction in SCAs. A clinical study, performed on 21 Cuban SCA2 patients in an advanced disease stage, showed constant signs of dysautonomia, the most frequent features being orthostatic hypotension (95%), constipation (90%), distal coldness (57%), urinary incontinence (52%), and increased lacrimation (52%) [5]. Dysautonomic features (dysuria, constipation, and sexual dysfunction) have been described in a patient affected with SCA17, mimicking the cerebellar form of multiple system atrophy [11]. 123 I-MIBG myocardial uptake scintigraphy and sympathetic skin response have been investigated in 19 SCA3 patients, showing cardiac and sudomotor sympathetic dysfunction [12]. Another study assessed autonomic function in 15 SCA3 patients, using a questionnaire and two electrophysiological tests [6]. The most frequent reported abnormalities were nocturia, cold intolerance, and orthostatic dizziness, present in about half of patients. Prolonged latency or absence of sympathetic skin response to electrical stimulation and abnormal R–R interval variation were identified in more than 70% of the patients. The present study is the first neurophysiologic evaluation of ANS in patients with SCA2 through a complete battery of cardiovascular autonomic reflexes tests. Among them, head-up tilt, standing, and Valsalva manoeuvre are aimed to explore the integrity of the baroreflex arc, the last test mainly, but not exclusively, investigating the vagal component; gripping isometric exercise, cold pressure and arithmetic tests evaluate efferent sympathetic pathways; deep breathing and hyperventilation tests are useful to assess HR vagal control. We selected patients with mild to moderate disability to obtain full cooperation in performing the tests and to avoid secondary autonomic dysfunction due to prolonged lying position. Autonomic symptoms, investigated by a questionnaire, were common in our patients. All complained of urinary tract dysfunction, eight reported postural hypotension symptoms and seven gastrointestinal symptoms. Bladder and sexual dysfunction significantly contribute to the patients' disability. The cardiovascular neurophysiologic evaluation showed a high range variability of responses, with different degrees and combinations of autonomic abnormalities, in the absence of a typical pattern of dysfunction (Table 4). One patient (patient 9) had entirely normal tests. An initial ANS impairment was observed in patients 1, 2, 5, and 6, with exaggerated HR increase at some tests, but substantial preservation of the arterial baroreflex pathways. Finally, the abnormalities found in patients 3, 4, 7, and 8 are consistent with a prominent ANS failure with baroreflex arc dysfunction. Although a SCA2 specific pattern of ANS dysfunction did not stand out in our patients, a marked chronotropic cardiac response was often observed, in particular in the tilt, standing, hand gripping and
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hyperventilation tests. Increased tachycardia, which sometimes was above 110 bpm, may be related to an increased sympathetic outflow, rather than to a simple withdrawal of vagal tone. Since hypovolaemia, cardiomyopathy, and other non-neurogenic cause of ineffective BP control can be excluded in our patients, this amplified sympathetic response may be interpreted as compensatory to an initial autonomic impairment. A somewhat surprising result is the absence of correlation between ANS dysfunction in our patients and either molecular or clinical findings. Of course, the small number of patients and their relative homogeneity for clinical severity and expansion size could have prevented from observing significant correlations. Another possible explanation is that the progression of ANS dysfunction does not parallel the neurodegeneration processes which cause the motor defects. It is interesting to note that a correlation between clinical features and autonomic involvement was not evident in a patho-anathomical study in six SCA2 patients [13]. This study also showed complete sparing of the autonomic nuclei in the patient with the latest onset (55 years). Similarly, we observed normal neurophysiologic evaluation in patient 9, the individual with the latest onset in our series. The main cerebral areas involved in autonomic system regulation are the hypothalamus and a few nuclei of brainstem, such as the locus coeruleus (LC), the nucleus tractus solitarius (NTS), the nucleus ambiguus (NA), the dorsal motor nucleus of the vagus (DMV), the rostral ventrolateral medulla (RVLM) neurons, the pontine micturition center (Barrington's nucleus, PMC), and the reticular paramedian nucleus (RPN). The NTS is a key component of the central pathway for cardiovascular regulation, acting as a terminal for primary baroreceptor afferents. The sympathetic output to the heart is through the RPN, whereas the ventrolateral portion of NA provides most of the vagal output, with less contributions from DMV, which is considered to be mainly responsible for gastrointestinal motility. RVLM projects to sympathetic preganglionic neurones and is critical for the tonic and reflex control of arterial pressure. PMC projects to both the LC and preganglionic column of the lumbosacral spinal cord, coordinating brain noradrenergic activity with pelvic visceral functions. LC has a role in bladder and cardiovascular control, in particular in the arousal caused by bladder distension. Pathological studies on SCA2 are rare and often omit examination of the autonomic nuclei. Little neuronal loss has been reported in the LC of seven patients from the Cuban cluster of families, which later has been shown to be affected with SCA2 [14]. A more recent study investigated some brainstem autonomic nuclei in patients with SCA2, demonstrating moderate to severe cell loss and astrogliosis of NTS, NA, and DMV in five of six patients [13]. Atrophy and demyelination of autonomic fiber tracts were also found. The prominent involvement of NTS, NA, and DMV may be related to cardiovagal failure and abnormal gastrointestinal motility of SCA2 patients.
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As far as we know, degeneration of PMC and other pontine structures regulating bladder voiding has not been investigated in SCA2, however, as suggested by constant pons atrophy at MRI, their involvement is likely. The inhibitory input loss of the PMC could explain a detrusoral hyperreflessia causing urgency and incontinence. Although the degeneration of brainstem autonomic nuclei may well explain dysautonomia in SCA2, the almost constant sensorymotor axonal neuropathy described in these patients also may play an important role in the autonomic dysfunction of SCA2 patients. Skin biopsies to examine autonomic cutaneous nerve fibers, small fiber electrophysiological studies, and 123I-MIBG myocardial uptake scintigraphic examinations should be performed in these patients to correlate the results with the autonomic abnormalities. References [1] Schols L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 2004;3: 291–304. [2] Filla A, Mariotti C, Caruso G, Coppola G, Cocozza S, Castaldo I, et al. Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families. Eur Neurol 2000;44:31–6. [3] Pulst SM, Nechiporuk T, Nechiporuk A, Gispert S, Chen XN, Lopes-Cendes I, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 1996;4:269–76. [4] Filla A, De Michele G, Santoro L, Calabrese O, Castaldo I, Giuffrida S, et al. Spinocerebellar ataxia type 2 in southern Italy: a clinical and molecular study of 30 families. J Neurol 1999;246:467–71. [5] Sanchez-Cruz G, Velazquez-Perez L, Gomez-Pena L, Martinez-Gongora E, Castellano-Sanchez G, Santos-Falcon N. Dysautonomic features in patients with Cuban type 2 spinocerebellar ataxia. Rev Neurol 2001;33:428–34. [6] Yeh TH, Lu CS, Chou YH, Chong CC, Wu T, Han NH, et al. Autonomic dysfunction in Machado–Joseph disease. Arch Neurol 2005;62:630–6. [7] Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci 1997;145:205–11. [8] Petretta M, Marciano F, Bianchi V, Migaux ML, Valva G, De Luca N, et al. Power spectral analysis of heart period variability in hypertensive patients with left ventricular hypertrophy. Am J Hypertens 1995;8:1206–13. [9] Mathias CJ, Bannister R. Investigations of autonomic disorders. In: Bannister R, Mathias CJ, editors. Autonomic Failure. Oxford: Oxford University Press; 1999. p. 169–95. [10] Del Sorbo F, Elia AE, De Joanna G, Romito LM, Garavaglia B, Albanese A. Normal cardiovascular reflex testing in patients with parkin disease. Mov Disord 2007;22: 528–32. [11] Lin IS, Wu RM, Lee-Chen GJ, Shan DE, Gwinn-Hardy K. The SCA17 phenotype can include features of MSA-C, PSP and cognitive impairment. Parkinsonism Relat Disord 2007;13:246–9. [12] Kazuta T, Hayashi M, Shimizu T, Iwasaki A, Nakamura S, Hirai S. Autonomic dysfunction in Machado–Joseph disease assessed by iodine123-labeled metaiodobenzylguanidine myocardial scintigraphy. Clinic Auton Res 2000;10:111–5. [13] Gierga K, Burk K, Bauer M, Orozco Diaz G, Auburger G, Schultz C, et al. Involvement of the cranial nerves and their nuclei in spinocerebellar ataxia type 2 (SCA2). Acta Neuropathol (Berl) 2005;109:617–31. [14] Orozco G, Estrada R, Perry TL, Araña J, Fernandez R, Gonzalez-Quevedo A, et al. Dominantly inherited olivopontocerebellar atrophy from eastern Cuba. Clinical, neuropathological, and biochemical findings. J Neurol Sci 1989;93:37–50.