Journal of the Autonomic Nervous System, 39 (1992) 29-36
29
© 1992 Elsevier Science Publishers B.V. All rights reserved 0165-1838/92/$05.00 JAN'S 01273
Autonomic cardiovascular reflexes in progressive supranuclear palsy * Jos~ A. G u t r e c h t Department of Neurology, Lahey Clinic Medical Center, Burlington, Massachusetts, USA (Received 25 October 1991) (Revision received and accepted 15 February 1992)
Key words: Progressive supranuclear palsy; Autonomic cardiovascular reflex Abstract Assessment of possible autonomic nervous system dysfunction was performed by testing cardiovascular reflexes in nine patients with progressive supranuclear palsy (PSP). The patients were significantly different from 15 control age-matched subjects because of greater blood pressure drop on standing for 1 min, diminished rise of diastolic blood pressure during the sustained handgrip test, and lack of compensatory tachycardia measured by the 30 : 15 ratio on standing. The latter test abnormality was caused by a slow rise to erect posture. No differences were observed in the cold pressor test, Valsalva ratio, and heart rate response to deep breathing. The differences between patients and control subjects were usually small. Autonomic nervous system involvement in patients with PSP is minor and is caused by involvement of central brain stem sympathetic nuclei or efferent fibers.
Introduction Progressive supranuclear palsy (PSP), also known as Steele-Richardson-Olszewski syndrome, consists of supranuclear ophthalmoplegia and at least two or more of the following features: axial dystonia and rigidity, pseudobulbar palsy, bradykinesia, frontal lobe deficits, and postural instability [29]. Extensive clinical reviews [1,5,7,18,19,26,29,33,42,43] of PSP have described many features but none suggestive of autonomic nervous system dysfunction except for bowel and bladder difficulties in rare cases [18,19,33]. No
Correspondence: J.A. Gutrecht, Department of Neurology, Lahey Clinic Medical Center, 41 Mall Road, Burlington, MA 01805, USA. * This paper was presented in part at the 14th World Congress of Neurology, New Delhi, India, October 23, 1989.
reports of autonomic nervous system dysfunction in patients with PSP are available despite the fact that the pathological features of the illness include neuronal cell loss, gliosis, and atypical neurofibrillary tangles in areas commonly associated with the autonomic nervous system [3,17,2124,27,36,41,44,46]. Assessment of possible autonomic nervous system dysfunction was performed by studying bedside non-invasive cardiovascular reflexes [8] in nine patients with PSP.
Materials and Methods Five women and four men with the classic features of PSP were studied. They had no evidence of peripheral neuropathy, hypovolemia, or other disease that may cause autonomic nervous system dysfunction. The median age was 71 years
30 TABLE I
Demographic data for patients" with progressive supranuclear palsy Patient no.
Age (yrs)
Sex
Duration of PSP (yrs)
Hoehn and Yahr score
1 2 3 4 5 6 7 8 9
68 76 71 66 68 71 84 76 69
F F M F M M F F M
2 6 2 5 3 4 3 5 4
3 5 2 3 4 2 4 4 3
(range 66-84 years), and the mean duration of the illness was 3.6 years (range 2 - 6 years). The severity of the illness varied from mild in two patients to severe in one patient (average Hoehn and Yahr [15] score 3.33; median score 3.0) (Table I). None of the patients was bedridden. Two patients were receiving thyroid supplement and were biochemically euthyroid. None of the patients was taking levodopa, dopamine receptor agonists, or antihypertensive medication for at least 2 weeks before the time of testing. The following cardiovascular r.eflexes were studied: Orthostatic blood pressure measurements. The supine baseline arterial systolic and diastolic blood pressures were measured after the patient rested for at least 10 m i n and at 1 m i n after standing [8,31]. Sustained handgrip test. Baseline arterial blood pressure was measured. The maximal voluntary dominant handgrip contraction was determined as the patient squeezed a partially inflated blood pressure cuff for a few seconds and sustained the grip at a closely monitored 30% of the maximal value for the next 5 min. Blood pressure was measured in the other arm every minute for 5 rain. The systolic and diastolic values were compared with the baseline (resting) value [11]. Cold pressor test. With the patient supine, the baseline blood pressure was measured. One hand
was then placed in cold (approximately 4°C) water for 1 min, and the blood pressure was measured at 60 s [11,14,31]. Valsalva ratio. The Valsalva maneuver was performed separately for 10 and 15 s with the patient sitting, maintaining an expiratory pressure of 40-50 mmHg as measured with an aneroid manometer. Electrocardiography (EKG) was simultaneously recorded. The ratio was calculated by dividing the longest R-R peaks interval after the maneuver (phase IV) by the shortest R-R interval during the maneuver (phase II) [30]. Heart rate response to standing (30:15 ratio). Electrocardiography was performed while the patient stood after 5 rain of resting supine. The ratio of the 30th R-R interval over the 15th R-R interval beginning from the moment the patient started to stand up was calculated [9,10]. Heart rate response to deep breathing. The patient was trained to inhale and exhale deeply for 5 s each (breathing rate 6 b r e a t h s / m i n ) for 1 rain during monitoring by EKG. The greatest difference between maximal and minimal heart rate was calculated [49]. Age-dependent changes in cardiovascular reflexes in the general population have been noted [20,32,40,48]. Thus, our patients were matched with an age-controlled group of 15 (nine men, six women) healthy subjects not taking any medication. Differences between the patient group and control group were analyzed for significance using the unpaired Student's t-test (age, baseline blood pressure, heart rate, orthostatic blood pressure, deep breathing response, cold pressor response, and sustained handgrip response) and the Mann-Whitney rank sum test (30:15 ratio; 10-s and 15-s Valsalva ratios). Normal response values for each test were also calculated for the control group. The responses in patients with PSP, > 2 S.D. of the average values in the control group, were deemed borderline abnormal, and responses > 2.5 S.D. of the average values were considered abnormal. Eight of nine patients were able to perform all of the tests satisfactorily. One patient (Patient 2) was able to perform only three of the six tests, namely, the orthostatic blood pressure measurements, the cold pressor test, and the heart rate response to standing. All patients and con-
31 TABLE II
Comparison of patients with PSP with control subjects Patients with PSP Age (yrs ± S.D.)
Control subjects
72.1 ± 5.6
Blood pressure Systolic * Diastolic *
150 80
Baseline heart rate ÷
69.5 ±
-1- 19 + 7
141 86
74.8 ± 11
P Value
7.4
NS *
+ 22 ± 11
NS * NS *
74.1 + 11
NS ~
Drop in blood pressure at 1 min Systolic * Diastolic *
8.6 ± 8.0 3.4 ± 5.0
2.9 ± 4.1 0.3 + 1.0
P=0.03 P = 0.03
30:15 ratio
1.05 ± 0.05
1.10 ± 0.06
P = 0.02 §
Valsalva ratio 10s 15 s
1.18± 0.I1 1.20 ± 0.09
1.24± 0.08 1.27 ± 0.05
NS § NS ~
Deep breathing heart rate response +
14.9 +
8.3
18.6 ± 4.0
NS *
Sustained handgrip response Systolic * Diastolic *
18.8 + 8.7 10.3 ± 5.6
23.7 ± 7.9 17.6 ± 4:9
NS * P=0.004
Cold pressor blood pressure response Systolic * Diastolic *
22.4 + 13.9 12.2 ± 6.0
14.9 ± 7.2 10.8 ± 3.8
NS t NS *
PSP = Progressive supranuclear palsy. * mmHg + S.D. + B e a t s / m i n ± S.D. *NS = P > 0.05. ~ Mann-Whitney test.
TABLE III
Results of cardiovascular reflex tests Patient no.
Hoehn and Yahr score
Orthostatic blood pressure drop at 1 rain
Sustained handgrip response
Cold pressor blood pressure response
Systolic
1 2 3 4 5 6 7 8 9
3 5 2 3 4 2 4 4 3
Ab N Ab N BAb N Ab Ab N
Diastolic
Systolic
Diastolic
Systolic
Diastolic
N N Ab N N N Ab Ab N
Ab U N N N N N N N
Ab U N N N BAb N N N
N N N N N N BAb N N
N N N N N N BAb N N
Valsalva ratio 30 : 15 10 s 15 s ratio
Deep breathing heart rate response
N N N N Ab N N N N
N U N N Ab N Ab Ab BAb
N U Ab N Ab N N N N
N N N N N N Ab N BAb
Ab = > 2.5 S.D. of Control subjects' average. BAb = > 2 S.D., < 2.5 S.D. of Control subjects' average. U ~ Unable to perform. N = Normal response.
32 trol subjects were tested after breakfast in the late morning.
Results No demographic data, baseline blood pressure, or heart rate differences were observed between patients with PSP and control subjects (Table II). Significant differences between patients with PSP and the control subjects were evident in the orthostatic drop in blood pressure, the change in heart rate after standing (30:15 ratio), and the diminished rise in diastolic blood pressure after sustained handgrip (Table II). However, no differences were noted in the Valsalva ratios (at 10 and 15 s), heart rate response to deep breathing, systolic blood pressure response to sustained handgrip, and blood pressure response in the cold pressor test. When results of each of the tests for individual patients were compared with results from the control group (Table III), the findings varied with one patient having no abnormal results (Patient 4) to another patient (Patient 7) having six abnormal results. No trend between the severity of the illness and individual test results could be discerned. Most patients did not have symptoms of autonomic system failure.
Discussion Central regulation of cardiovascular reflexes depends on baroreceptor reflexes subserved by neurons located primarily in the lower brain stem and spinal cord. The afferent limb of the arc consists of specialized baroreceptor neurons and their axons that enter the central nervous system with the cranial nerves IX and X and synapse in the nucleus of the tractus solitarius. The efferent limb is formed by preganglionic neurons located in the dorsal medulla (parasympathetic cardioinhibitory) and in the lateral medulla (sympathetic). The effector parasympathetic medullary neurons probably reside in the visceromotor vagal nucleus (dorsal motor nucleus) and exit the central nervous system in cranial nerve X. The effector sympathetic neurons are located in the lateral
medullary reticular formation (bulbospinal nucleus), and their axons descend in the lateral columns of the spinal cord to synapse with the preganglionic neurons in the intermediolateral nucleus between the first thoracic and second lumbar levels. The efferent fibers of the preganglionic neurons exit the central nervous system in the anterior spinal roots. Rich multisynaptic connections among these nuclei and other nuclei in the reticular formation and hypothalamus have been described [39,47]. Suprasegmental connection from the limbic system, hypothalamus, and reticular formation thus exerts important excitatory and inhibitory modulating influences on the baroreceptor reflexes [34,39,47]. The response of the blood pressure to standing, the simplest and most commonly used test for autonomic nervous system dysfunction, showed a significantly greater but small drop at 1 min in patients with PSP than in control subjects (P = 0.03). It was the most common finding in the present study; it occurred in five of the nine patients. It is usually accepted that postural hypotension is the result of lesion(s) affecting the efferent vasomotor fibers provided the patient is not taking antihypertensive medication or in the presence of hypovolemia or adrenal insufficiency [31,35]. In most instances of neurogenic postural hypotension, the lesions involve the peripheral nerves or the intermediolateral nucleus of the spinal cord [31,35,38,45]. In autopsy studies of the spinal cord of patients with PSP, few changes and no neuronal loss have been documented in the intermediolateral columns [1,5,21,22,26,36,44,46], and none of our patients had peripheral neuropathy. Of more importance, neuronal loss, gliosis, and atypical neurofibriUary tangles in the hypothalamus, periaqueductal gray matter, and pontine and medullary reticular formation have frequently been reported [1,5,17,21-24,27,29,4144,46]. These are areas known to be involved in the normal physiology of the autonomic nervous system [4,25,34,39,47]. Disruption of these areas has been suggested as responsible for the autonomic nervous system dysfunction in patients with Parkinson's disease [28], brain stem glioma [16], and syringobulbia [37]. Thus, it is suggested that in patients with PSP, the lesion in the efferent
33
sympathetic system responsible for the postural hypotension is located in the hypothalamic efferents or in the medullary reticular formation efferent neurons. The diminished rise of the diastolic blood pressure in the closely monitored sustained handgrip test in our patients (P = 0.004) may also be the result of the failure of central sympathetic neurons because the role of this system in this test is well accepted [12,13]. The 30:15 ratio describes the immediate heart rate increase followed by a heart rate decrease in response to standing. Significant differences were noted between patients with PSP and control subjects in this test (P = 0.02). The control subjects stood up promptly. Thus, the differences between these two groups are likely to be the result of the slowness in standing up because a '35:20' ratio showed no differences. No significant differences were noted in the results of the cold pressor test between the patients with PSP and the control group. In fact, this test resulted in a higher but still insignificant rise in blood pressure in the patient group. This finding would again suggest that the pathways of the cold pressor reflex arc in patients with PSP may not be involved. The higher rise in blood pressure is of interest; it would agree with the concept of decentralization suprasensitivity [6,31] of the peripheral sympathetic nervous system after lesions of the central sympathetic neuronal pathways. The Valsalva maneuver is a frequently used test of baroreceptor integrity. The complex hemodynamic changes occurring during this maneuver are usually measured in terms of blood pressure and heart rate changes [2,8]. The Valsalva ratio reflects only heart rate changes and is derived by dividing the longest R-R interval, which occurs in phase IV (after strain), by the shortest R-R interval in phase II of the maneuver. This ratio has commonly been used as a test of vagal function. No differences were noted between the patients with PSP and the control subjects. The response of heart rate to deep breathing is considered a highly sensitive test for vagal integrity [8]. This test revealed no differences between patients in the PSP group and subjects
in the control group and therefore suggests intact vagal function in patients with PSP. However, results of this test were abnormal in four of the patients with PSP. Neuropathological studies occasionally demonstrate lesions in the dorsal motor nucleus of the vagal nerve [3,22,27, 36,42]. It is suggested that the changes in this nucleus may not reach a critical level in every patient or represent an inconstant pathological feature in patients with PSP. Symptoms of postural hypotension were not reported by the patients. This finding agrees with the usually mild blood pressure drop on standing. However, blood pressure measurements taken with the patient supine and after standing should be obtained in patients with PSP. It was the most common abnormal finding, and it could result in added disability to the assumption of erect posture and initiation of walking. The mild but significant abnormalities in cardiovascular reflexes observed in patients with PSP suggest the presence of autonomic sympathetic central nervous system pathological findings. Lack of severity or universal involvement in patients with PSP may reflect absence in some patients or partial involvement of specific sympathetic hypothalamic brain stem efferents and their connections on the intermediolateral column neurons in the spinal cord.
Acknowledgement The technical assistance of Ms. Maureen P.D. Murray is appreciated.
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20 Kaijser, L. and Sachs, C., Autonomic cardiovascular responses in old age, Clin. Physiol., 5 (1985) 347-357. 21 Kato, T., Hirano, A., Weinberg, M.N. and Jacobs, A.K., Spinal cord lesions in progressive supranuclear palsy: some new observations, Acta Neuropathol. (Berl.), 71 (1986) 11-14. 22 Kida, M., Koo, H., Grossniklaus, H.E. and Tomsak, R.L., Neuropathologic findings in progressive supranuclear palsy: a brief review with two additional case reports, J. Clin. Neuro. Ophthalmol., 8 (1988) 161-170. 23 Kish, S.J., Chang, L.J., Mirchandani, L., Shannak, K. and Hornykiewicz, O., Progressive supranuclear palsy: relationship between extrapyramidal disturbances, dementia and brain neurotransmitter markers, Ann. Neurol., 18 (1985) 530-536. 24 Koeppen, A.H. and Hans, M.B., Supranuclear ophthalmoplegia in olivopontocerebellar degeneration, Neurology, 26 (1976) 764-768. 25 Korner, P.I., Central nervous control of autonomic cardiovascular function. In R.M. Berne and N. Sperelakis (Eds.), Handbook of Physiology: A Critical, Comprehensive Presentation of Physiological Knowledge and Concepts, Vol. 1, American Physiological Society, Bethesda, 1979, pp. 691-739. 26 Kristensen, M.O., Progressive supranuclear palsy--20 years later, Acta Neurol. Scand., 71 (1985) 177-189. 27 Kurihara, T., Landau, W.M. and Torack, R.M., Progressive supranuclear palsy with action myoclonus, seizures, Neurology, 24 (1974) 219-223. 28 Langston, J.W. and Forno, L.S., The hypothalamus in Parkinson disease, Ann. Neurol., 3 (1978) 129-133. 29 Lees, A.J., The Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). In C.D. Marsden and S. Fahn (Eds.), Movement Disorders 2, Butterworths, London, 1987, pp. 272-287. 30 Levin, A.B., A simple test of cardiac function based upon the heart rate changes induced by the Valsalva maneuver, Am. J. Cardiol., 18 (1966) 90-99. 31 Low, P.A., Quantitation of autonomic responses. In P.J. Dyck, P.K. Thomas, E.H. Lambert and R. Bunge (Eds), Peripheral Neuropathy, Saunders, Philadelphia, 1984, pp. 1139-1165. 32 Low, P.A., Opfer-Gehrking, T.L., Proper, C.J. and Zimmerman, I., The effect of aging on cardiac autonomic and postganglionic pseudomotor function, Muscle Nerve, 13 (1990) 152-157. 33 Maher, E.R. and Lees, A.J., The clinical features and natural history of the Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy), Neurology, 36 (1986) 1005-1008. 34 McLeod, J.G. and Tuck, R.R., Disorders of the autonomic nervous system: part 1. Pathophysiology and clinical features, Ann. Neurol., 21 (1987) 419-430. 35 McLeod, J.G. and Tuck, R.R., Disorders of the autonomic nervous system: part 2. Investigation and treatment, Ann. Neurol., 21 (1987) 519-529.
35 36 Mori, H., Yoshimura, M., Tomonaga, M. and Yamanouchi, H., Progressive supranuclear palsy with Lewy bodies, Acta Neuropathol. (Berl.), 71 (1986) 344-346. 37 Nogu6s, M.A., Newman, P.K., Male, V.J. and Foster, J.B., Cardiovascular reflexes in syringomyelia, Brain, 105 (1982) 835-849. 38 Oppenheimer, D., Neuropathology of progressive autonomic failure. In R. Bannister (Ed.), Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, Oxford University Press, Oxford, 1983, pp. 267-283. 39 Palkovits, M. and Z~borszky, L., Neuroanatomy of central cardiovascular control. Nucleus tractus solitarii: afferent and efferent neuronal connections in relation to the baroreceptor reflex arc. In W. De Jong, A.P. Provoost and A.P. Shapiro (Eds.), Progressive Brain Research, Elsevier, Amsterdam, 1977, 47, pp. 9-34. 40 Pfeifer, M.A., Weinberg, C.R., Cook, D., Best, J.D., Reenan, A. and Halter, J.B., Differential changes of autonomic nervous system function with age in man, Am. J. Med., 75 (1983) 249-258. 41 Powell, H.C., London, G.W. and Lampert, P.W., Neurofibrillary tangles in I~rogressive supranuclear palsy: electron microscope observations, J. Neuropath. Exp. Neurot., 33 (1974) 98-106. o
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29
© 1992 Elsevier Science Publishers B.V. All rights reserved 0165-1838/92/$05.00 JAN'S 01273
Autonomic cardiovascular reflexes in progressive supranuclear palsy * Jos~ A. G u t r e c h t Department of Neurology, Lahey Clinic Medical Center, Burlington, Massachusetts, USA (Received 25 October 1991) (Revision received and accepted 15 February 1992)
Key words: Progressive supranuclear palsy; Autonomic cardiovascular reflex Abstract Assessment of possible autonomic nervous system dysfunction was performed by testing cardiovascular reflexes in nine patients with progressive supranuclear palsy (PSP). The patients were significantly different from 15 control age-matched subjects because of greater blood pressure drop on standing for 1 min, diminished rise of diastolic blood pressure during the sustained handgrip test, and lack of compensatory tachycardia measured by the 30 : 15 ratio on standing. The latter test abnormality was caused by a slow rise to erect posture. No differences were observed in the cold pressor test, Valsalva ratio, and heart rate response to deep breathing. The differences between patients and control subjects were usually small. Autonomic nervous system involvement in patients with PSP is minor and is caused by involvement of central brain stem sympathetic nuclei or efferent fibers.
Introduction Progressive supranuclear palsy (PSP), also known as Steele-Richardson-Olszewski syndrome, consists of supranuclear ophthalmoplegia and at least two or more of the following features: axial dystonia and rigidity, pseudobulbar palsy, bradykinesia, frontal lobe deficits, and postural instability [29]. Extensive clinical reviews [1,5,7,18,19,26,29,33,42,43] of PSP have described many features but none suggestive of autonomic nervous system dysfunction except for bowel and bladder difficulties in rare cases [18,19,33]. No
Correspondence: J.A. Gutrecht, Department of Neurology, Lahey Clinic Medical Center, 41 Mall Road, Burlington, MA 01805, USA. * This paper was presented in part at the 14th World Congress of Neurology, New Delhi, India, October 23, 1989.
reports of autonomic nervous system dysfunction in patients with PSP are available despite the fact that the pathological features of the illness include neuronal cell loss, gliosis, and atypical neurofibrillary tangles in areas commonly associated with the autonomic nervous system [3,17,2124,27,36,41,44,46]. Assessment of possible autonomic nervous system dysfunction was performed by studying bedside non-invasive cardiovascular reflexes [8] in nine patients with PSP.
Materials and Methods Five women and four men with the classic features of PSP were studied. They had no evidence of peripheral neuropathy, hypovolemia, or other disease that may cause autonomic nervous system dysfunction. The median age was 71 years
30 TABLE I
Demographic data for patients" with progressive supranuclear palsy Patient no.
Age (yrs)
Sex
Duration of PSP (yrs)
Hoehn and Yahr score
1 2 3 4 5 6 7 8 9
68 76 71 66 68 71 84 76 69
F F M F M M F F M
2 6 2 5 3 4 3 5 4
3 5 2 3 4 2 4 4 3
(range 66-84 years), and the mean duration of the illness was 3.6 years (range 2 - 6 years). The severity of the illness varied from mild in two patients to severe in one patient (average Hoehn and Yahr [15] score 3.33; median score 3.0) (Table I). None of the patients was bedridden. Two patients were receiving thyroid supplement and were biochemically euthyroid. None of the patients was taking levodopa, dopamine receptor agonists, or antihypertensive medication for at least 2 weeks before the time of testing. The following cardiovascular r.eflexes were studied: Orthostatic blood pressure measurements. The supine baseline arterial systolic and diastolic blood pressures were measured after the patient rested for at least 10 m i n and at 1 m i n after standing [8,31]. Sustained handgrip test. Baseline arterial blood pressure was measured. The maximal voluntary dominant handgrip contraction was determined as the patient squeezed a partially inflated blood pressure cuff for a few seconds and sustained the grip at a closely monitored 30% of the maximal value for the next 5 min. Blood pressure was measured in the other arm every minute for 5 rain. The systolic and diastolic values were compared with the baseline (resting) value [11]. Cold pressor test. With the patient supine, the baseline blood pressure was measured. One hand
was then placed in cold (approximately 4°C) water for 1 min, and the blood pressure was measured at 60 s [11,14,31]. Valsalva ratio. The Valsalva maneuver was performed separately for 10 and 15 s with the patient sitting, maintaining an expiratory pressure of 40-50 mmHg as measured with an aneroid manometer. Electrocardiography (EKG) was simultaneously recorded. The ratio was calculated by dividing the longest R-R peaks interval after the maneuver (phase IV) by the shortest R-R interval during the maneuver (phase II) [30]. Heart rate response to standing (30:15 ratio). Electrocardiography was performed while the patient stood after 5 rain of resting supine. The ratio of the 30th R-R interval over the 15th R-R interval beginning from the moment the patient started to stand up was calculated [9,10]. Heart rate response to deep breathing. The patient was trained to inhale and exhale deeply for 5 s each (breathing rate 6 b r e a t h s / m i n ) for 1 rain during monitoring by EKG. The greatest difference between maximal and minimal heart rate was calculated [49]. Age-dependent changes in cardiovascular reflexes in the general population have been noted [20,32,40,48]. Thus, our patients were matched with an age-controlled group of 15 (nine men, six women) healthy subjects not taking any medication. Differences between the patient group and control group were analyzed for significance using the unpaired Student's t-test (age, baseline blood pressure, heart rate, orthostatic blood pressure, deep breathing response, cold pressor response, and sustained handgrip response) and the Mann-Whitney rank sum test (30:15 ratio; 10-s and 15-s Valsalva ratios). Normal response values for each test were also calculated for the control group. The responses in patients with PSP, > 2 S.D. of the average values in the control group, were deemed borderline abnormal, and responses > 2.5 S.D. of the average values were considered abnormal. Eight of nine patients were able to perform all of the tests satisfactorily. One patient (Patient 2) was able to perform only three of the six tests, namely, the orthostatic blood pressure measurements, the cold pressor test, and the heart rate response to standing. All patients and con-
31 TABLE II
Comparison of patients with PSP with control subjects Patients with PSP Age (yrs ± S.D.)
Control subjects
72.1 ± 5.6
Blood pressure Systolic * Diastolic *
150 80
Baseline heart rate ÷
69.5 ±
-1- 19 + 7
141 86
74.8 ± 11
P Value
7.4
NS *
+ 22 ± 11
NS * NS *
74.1 + 11
NS ~
Drop in blood pressure at 1 min Systolic * Diastolic *
8.6 ± 8.0 3.4 ± 5.0
2.9 ± 4.1 0.3 + 1.0
P=0.03 P = 0.03
30:15 ratio
1.05 ± 0.05
1.10 ± 0.06
P = 0.02 §
Valsalva ratio 10s 15 s
1.18± 0.I1 1.20 ± 0.09
1.24± 0.08 1.27 ± 0.05
NS § NS ~
Deep breathing heart rate response +
14.9 +
8.3
18.6 ± 4.0
NS *
Sustained handgrip response Systolic * Diastolic *
18.8 + 8.7 10.3 ± 5.6
23.7 ± 7.9 17.6 ± 4:9
NS * P=0.004
Cold pressor blood pressure response Systolic * Diastolic *
22.4 + 13.9 12.2 ± 6.0
14.9 ± 7.2 10.8 ± 3.8
NS t NS *
PSP = Progressive supranuclear palsy. * mmHg + S.D. + B e a t s / m i n ± S.D. *NS = P > 0.05. ~ Mann-Whitney test.
TABLE III
Results of cardiovascular reflex tests Patient no.
Hoehn and Yahr score
Orthostatic blood pressure drop at 1 rain
Sustained handgrip response
Cold pressor blood pressure response
Systolic
1 2 3 4 5 6 7 8 9
3 5 2 3 4 2 4 4 3
Ab N Ab N BAb N Ab Ab N
Diastolic
Systolic
Diastolic
Systolic
Diastolic
N N Ab N N N Ab Ab N
Ab U N N N N N N N
Ab U N N N BAb N N N
N N N N N N BAb N N
N N N N N N BAb N N
Valsalva ratio 30 : 15 10 s 15 s ratio
Deep breathing heart rate response
N N N N Ab N N N N
N U N N Ab N Ab Ab BAb
N U Ab N Ab N N N N
N N N N N N Ab N BAb
Ab = > 2.5 S.D. of Control subjects' average. BAb = > 2 S.D., < 2.5 S.D. of Control subjects' average. U ~ Unable to perform. N = Normal response.
32 trol subjects were tested after breakfast in the late morning.
Results No demographic data, baseline blood pressure, or heart rate differences were observed between patients with PSP and control subjects (Table II). Significant differences between patients with PSP and the control subjects were evident in the orthostatic drop in blood pressure, the change in heart rate after standing (30:15 ratio), and the diminished rise in diastolic blood pressure after sustained handgrip (Table II). However, no differences were noted in the Valsalva ratios (at 10 and 15 s), heart rate response to deep breathing, systolic blood pressure response to sustained handgrip, and blood pressure response in the cold pressor test. When results of each of the tests for individual patients were compared with results from the control group (Table III), the findings varied with one patient having no abnormal results (Patient 4) to another patient (Patient 7) having six abnormal results. No trend between the severity of the illness and individual test results could be discerned. Most patients did not have symptoms of autonomic system failure.
Discussion Central regulation of cardiovascular reflexes depends on baroreceptor reflexes subserved by neurons located primarily in the lower brain stem and spinal cord. The afferent limb of the arc consists of specialized baroreceptor neurons and their axons that enter the central nervous system with the cranial nerves IX and X and synapse in the nucleus of the tractus solitarius. The efferent limb is formed by preganglionic neurons located in the dorsal medulla (parasympathetic cardioinhibitory) and in the lateral medulla (sympathetic). The effector parasympathetic medullary neurons probably reside in the visceromotor vagal nucleus (dorsal motor nucleus) and exit the central nervous system in cranial nerve X. The effector sympathetic neurons are located in the lateral
medullary reticular formation (bulbospinal nucleus), and their axons descend in the lateral columns of the spinal cord to synapse with the preganglionic neurons in the intermediolateral nucleus between the first thoracic and second lumbar levels. The efferent fibers of the preganglionic neurons exit the central nervous system in the anterior spinal roots. Rich multisynaptic connections among these nuclei and other nuclei in the reticular formation and hypothalamus have been described [39,47]. Suprasegmental connection from the limbic system, hypothalamus, and reticular formation thus exerts important excitatory and inhibitory modulating influences on the baroreceptor reflexes [34,39,47]. The response of the blood pressure to standing, the simplest and most commonly used test for autonomic nervous system dysfunction, showed a significantly greater but small drop at 1 min in patients with PSP than in control subjects (P = 0.03). It was the most common finding in the present study; it occurred in five of the nine patients. It is usually accepted that postural hypotension is the result of lesion(s) affecting the efferent vasomotor fibers provided the patient is not taking antihypertensive medication or in the presence of hypovolemia or adrenal insufficiency [31,35]. In most instances of neurogenic postural hypotension, the lesions involve the peripheral nerves or the intermediolateral nucleus of the spinal cord [31,35,38,45]. In autopsy studies of the spinal cord of patients with PSP, few changes and no neuronal loss have been documented in the intermediolateral columns [1,5,21,22,26,36,44,46], and none of our patients had peripheral neuropathy. Of more importance, neuronal loss, gliosis, and atypical neurofibriUary tangles in the hypothalamus, periaqueductal gray matter, and pontine and medullary reticular formation have frequently been reported [1,5,17,21-24,27,29,4144,46]. These are areas known to be involved in the normal physiology of the autonomic nervous system [4,25,34,39,47]. Disruption of these areas has been suggested as responsible for the autonomic nervous system dysfunction in patients with Parkinson's disease [28], brain stem glioma [16], and syringobulbia [37]. Thus, it is suggested that in patients with PSP, the lesion in the efferent
33
sympathetic system responsible for the postural hypotension is located in the hypothalamic efferents or in the medullary reticular formation efferent neurons. The diminished rise of the diastolic blood pressure in the closely monitored sustained handgrip test in our patients (P = 0.004) may also be the result of the failure of central sympathetic neurons because the role of this system in this test is well accepted [12,13]. The 30:15 ratio describes the immediate heart rate increase followed by a heart rate decrease in response to standing. Significant differences were noted between patients with PSP and control subjects in this test (P = 0.02). The control subjects stood up promptly. Thus, the differences between these two groups are likely to be the result of the slowness in standing up because a '35:20' ratio showed no differences. No significant differences were noted in the results of the cold pressor test between the patients with PSP and the control group. In fact, this test resulted in a higher but still insignificant rise in blood pressure in the patient group. This finding would again suggest that the pathways of the cold pressor reflex arc in patients with PSP may not be involved. The higher rise in blood pressure is of interest; it would agree with the concept of decentralization suprasensitivity [6,31] of the peripheral sympathetic nervous system after lesions of the central sympathetic neuronal pathways. The Valsalva maneuver is a frequently used test of baroreceptor integrity. The complex hemodynamic changes occurring during this maneuver are usually measured in terms of blood pressure and heart rate changes [2,8]. The Valsalva ratio reflects only heart rate changes and is derived by dividing the longest R-R interval, which occurs in phase IV (after strain), by the shortest R-R interval in phase II of the maneuver. This ratio has commonly been used as a test of vagal function. No differences were noted between the patients with PSP and the control subjects. The response of heart rate to deep breathing is considered a highly sensitive test for vagal integrity [8]. This test revealed no differences between patients in the PSP group and subjects
in the control group and therefore suggests intact vagal function in patients with PSP. However, results of this test were abnormal in four of the patients with PSP. Neuropathological studies occasionally demonstrate lesions in the dorsal motor nucleus of the vagal nerve [3,22,27, 36,42]. It is suggested that the changes in this nucleus may not reach a critical level in every patient or represent an inconstant pathological feature in patients with PSP. Symptoms of postural hypotension were not reported by the patients. This finding agrees with the usually mild blood pressure drop on standing. However, blood pressure measurements taken with the patient supine and after standing should be obtained in patients with PSP. It was the most common abnormal finding, and it could result in added disability to the assumption of erect posture and initiation of walking. The mild but significant abnormalities in cardiovascular reflexes observed in patients with PSP suggest the presence of autonomic sympathetic central nervous system pathological findings. Lack of severity or universal involvement in patients with PSP may reflect absence in some patients or partial involvement of specific sympathetic hypothalamic brain stem efferents and their connections on the intermediolateral column neurons in the spinal cord.
Acknowledgement The technical assistance of Ms. Maureen P.D. Murray is appreciated.
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