Sudomotor, skin vasomotor, and cardiovascular reflexes in 3 clinical forms of Lewy body disease

Lewy body disease (LBD), which is characterized by the presence of Lewy bodies in the nervous system, represents several clinical forms, such as Parkinson disease without dementia (PD), Parkinson disease with dementia (PDD), dementia with Lewy bodies (DLB), and pure autonomic failure.^1–3 With regard to the pathologic staging of PD, a 6-stage system has been suggested to indicate a predictable sequence of lesions with ascending progression from the medullary (the dorsal motor nucleus of the glossopharyngeal and vagal nerves) and olfactory nuclei to the cortex. The first 2 presymptomatic stages are related to incidental LBD, stages 3 and 4 with motor symptoms, while the last 2 (cortical) stages may be frequently associated with cognitive impairment.^1,4 Although there has been a controversy as to whether the different clinical forms of LBD have similar cerebral Lewy body pathology, autonomic failure may clinically precede other neurologic features in LBD^5,6 as well as olfactory dysfunction.¹ On the other hand, the severity of cardiovascular autonomic dysfunction may be more severe in DLB/PDD than in PD.^7–9 However, differences in other autonomic dysfunctions, such as cardiac parasympathetic, sudomotor, and skin vasomotor dysfunctions, between DLB/PDD and PD have not been well investigated.

In PD, Lewy bodies are distributed in the hypothalamus, intermediolateral nucleus, sympathetic ganglia, dorsal vagal nucleus, and sacral parasympathetic nucleus.¹⁰ It is suggested that the lesions initially occur in the dorsal vagal and olfactory nucleus and progress to the substantia nigra, finally reaching the neocortical areas in PD.⁴ Lewy bodies may initially occur in the sympathetic ganglia, intermediolateral nucleus, and intramural ganglia.¹¹ These hypotheses have not been clinically well proven, although several studies using ¹²³I-MIBG scintigraphy indicated that cardiac sympathetic denervation occurs in early stage PD.¹²

In DLB, neuronal loss in the raphe nucleus, ventrolateral medulla, dorsal vagal nucleus, and locus ceruleus manifest as lesions in the central autonomic nervous system.¹³ Cardiac sympathetic denervation may occur in early stage DLB¹⁴ as well as PD. However, where Lewy body pathology begins and how it develops in DLB is currently unclear. Lewy body pathology in DLB may begin from dorsal vagal nucleus and olfactory nucleus or cardiac sympathetic neurons similar to PD, or progress in a manner different from PD.¹⁵

METHODS

Autonomic function tests.

The autonomic function tests were performed in a quiet room at an ambient temperature of 22-24° C. Each subject was asked to relax, stay awake, and remain in a supine position for at least 15 minutes before each test.

As indexes of cutaneous sympathetic function, sympathetic sweat response and skin vasomotor reflex were recorded.¹⁷ Sweat output was measured on the tip of the thumb (palm side) by a sudorometer (SKD-1000, Skinos, Nagano, Japan), and cutaneous blood flow was recorded at the tip of an index finger (palm side) by a Doppler flowmeter (ALF21D, Advance, Tokyo, Japan) during a sympathetic activation procedure that included deep inspiration, mental arithmetic, exercise (raising both lower limbs at 30° for 10 seconds), and tactile sensation (patient’s finger was rubbed by the examiner for 15 seconds). Figure 1 shows sweat output and cutaneous blood flow measurements in a healthy control subject. The sympathetic activation procedure increased sweat output (SSwR) and reduced cutaneous blood flow (SkVR). The SSwR amplitude was measured from the baseline to the peak, and the SkVR reduction rate (SkVR amplitude) was calculated as the percentage of reduced blood flow to basal blood flow [ (reduced flow/basal flow) × 100%]. SSwRs and SkVRs were considered absent when no responses were observed for any sympathetic activation tests. In normal controls, tactile sensation did not evoke SkVRs, and this factor was not considered when evaluating SkVRs.

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Figure 1 Recording of sympathetic sweat response (upper) and skin vasomotor reflex (lower) in a normal control subject (man, 67 years old)

Sweat output transiently increases and skin blood flow transiently decreases, while cutaneous blood flow is reduced, in response to the sympathetic activation procedures, including deep inspiration (DI), mental arithmetic (MA), exercise (Ex), and tactile sensation (TS).

The head-up tilt test was also performed. Blood pressure and heart rate were measured by a sphygmomanometer at 1-minute intervals. After 5 minutes of baseline measurement, each subject was passively tilted on an electrically driven tilt table at 70° for 10 minutes. We diagnosed orthostatic hypotension when patients showed a reduction in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing.

For evaluating the heart rate variability, electrocardiography was performed with the subjects in a supine position as 3 series of 100 consecutive R-R intervals with an accuracy of 1 msec during normal breathing in each subject. As an index of heart rate variability, the coefficient of variation of R-R intervals (CV_R-R) was calculated as the SD divided by the mean R-R interval. The average of the 3 series was used as the CV_R-R value. The abnormality of a CV_R-R value was judged according to age-dependent values (>1.18%; normal range in our laboratory).

RESULTS

There were no significant differences in age, disease duration, or Hoehn & Yahr stage among the DLB, PDD, and PD groups (table). The basal sweat output did not differ among the 4 groups (table). All controls subjects demonstrated SSwRs. Seven patients with DLB (58.3%), 6 patients with PDD (50.0%), and 3 patients with PD (25.0%) showed absence of SSwRs for any sympathetic activation procedures. Figure 2 shows mean SSwR amplitudes in the 4 groups. The SSwR amplitudes in the patients with DLB were lower than those in the controls for deep inspiration (p < 0.001), mental arithmetic (p < 0.0005), exercise (p < 0.0005), and tactile sensation (p < 0.0005). The SSwR amplitudes in the patients with PDD were lower than those in the controls for deep inspiration (p < 0.001), mental arithmetic (p < 0.0005), exercise (p < 0.0005), and tactile sensation (p < 0.0005). The SSwR amplitudes in the patients with PD were lower than those in the controls for deep inspiration (p < 0.01), mental arithmetic (p < 0.0005), exercise (p < 0.0005), and tactile sensation (p < 0.05). There were no significant differences among the 3 disorder groups for SSwR.

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Figure 2 Mean amplitudes of SSwRs for deep inspiration (A), mental arithmetic (B), exercise (C), and tactile sensation (D)

SSwR = sympathetic sweat response; DLB = dementia with Lewy bodies; PDD = Parkinson disease with dementia; PD = Parkinson disease without dementia. *p < 0.05 compared with the controls; **p < 0.01 compared with the controls; ***p < 0.001 compared with the controls.

The basal skin blood flow measurements did not differ among the 4 groups (table). All controls and patients with PD showed SkVRs. One patient with DLB (8%) and 3 patients with PDD (19.0%) showed no SkVRs for any procedures. The mean SkVR amplitudes in the 4 groups are shown in figure 3. The SkVR amplitudes in the patients with DLB were lower than those in the controls for deep inspiration (p < 0.05) and mental arithmetic (p < 0.05). Mean values in the patients with PDD were lower for mental arithmetic (p < 0.005) and tended to be lower for deep inspiration (p = 0.06) than in the controls, while mean values for mental arithmetic tended to be lower (p = 0.05) than in the patients with PD. The SkVR amplitudes in the patients with PD were not lower than those in the controls for any procedures.

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Figure 3 Mean reduction rates of SkVRs for deep inspiration (A), mental arithmetic (B), and exercise (C)

SkVR = skin vasomotor reflex; DLB = dementia with Lewy bodies; PDD = Parkinson disease with dementia; PD = Parkinson disease without dementia. *p < 0.05 compared with the controls; ***p < 0.001 compared with the controls.

In the head-up tilt test, systolic blood pressure and heart rate in the baseline supine position did not differ among the 4 groups. Diastolic blood pressure in the baseline supine position in the patients with DLB (p < 0.05) and patients with PDD (p < 0.05) was higher than that in the patients with PD (table).

Orthostatic hypotension was observed in 6 patients with DLB (50.0%), 8 patients with PDD (66.7%), and 3 patients with PD (25.0%). The mean decreases in systolic blood pressure during the head-up tilt test in the patients with DLB (p < 0.005) and patients with PDD (p < 0.05) were lower than in the controls. The mean decrease in diastolic blood pressure in patients with DLB was lower than that in controls (p < 0.001) or patients with PD (p < 0.01). The mean decrease in diastolic blood pressure in patients with PDD was lower than that in controls (p < 0.05). The mean change in heart rate during the head-up tilt test did not differ among the 4 groups (figure 4). Abnormally low values of CV_R-R were observed in 6 patients with DLB (50%), 3 patients with PDD (25%), and 3 patients with PD (25%). The mean CV_R-R value was lower in the patients with DLB (p < 0.005, figure 4).

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Figure 4 Mean changes in systolic (A) and diastolic (B) blood pressure and heart rate changes (C) during head-up tilt testing, and mean CV_R-R (D)

SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate; CV_RR = coefficient of variation of R-R interval; DLB = dementia with Lewy bodies; PDD = Parkinson disease with dementia; PD = Parkinson disease without dementia. *p < 0.05 compared with the controls; **p < 0.01 compared with the controls; ***p < 0.001 compared with the controls; †p < 0.01 compared with PD.

DISCUSSION

Our patients with Lewy body disorders showed prominently diminished SSwRs on the palm. This finding indicated a dysfunction of the so-called emotional sweating, which is observed on the glabrous skin of both the palm and plantar. There have been no reports on SSwR in patients with PD, except for one study,¹⁸ where SSwR amplitudes were shown to be reduced in patients with PD. Similar results have been reported in studies evaluating the sympathetic skin response,^19,20 which is considered a reflection of the electrical activity of the sweat glands. However, measurements of sympathetic skin responses are not quantitative, even though these measurements reflect emotional sweating as well as SSwR, which is actually a measurement of the amount of sweating. With regard to DLB and PDD, there have been no previous reports on SSwR or sympathetic skin responses. In our patients with Lewy body disorders, impairment of SSwRs seems to have been severe, particularly in patients with DLB and patients with PDD.

Our patients with DLB and patients with PDD showed attenuated SkVRs, although the patients with PD did not show a significant reduction in SkVRs. In a previous study, patients with PD did not show marked reduction in SkVRs.¹⁸ Although there has been no report on SkVRs in DLB or PDD, our results indicate that skin vasomotor function is impaired in DLB and PDD.

In our study, frequencies of orthostatic hypotension in patients with DLB (50.0%) and patients with PDD (66.7%) were high compared with the PD group (25.0%). The decrease in blood pressure during the head-up tilt test in patients with DLB and patients with PDD was greater compared to the patients with PD. In previous studies, orthostatic hypotension was observed in 20%-50% of patients with PD,^21–24 49% of patients with PDD,²⁵ and 50%-56% of patients with DLB.^7,8,25 The decrease in blood pressure during the head-up tilt test in our patients with DLB and patients with PDD was greater as compared to the patients with PD, and these results are in agreement with previous reports.^8,9 Baroreceptor reflex may be more severely disturbed in DLB and PDD compared with PD.

Our patients with DLB showed reduced CV_R-R values, which is an index of heart rate variability and mainly reflects cardiac parasympathetic function. Heart rate variability in PD has been reported to be normal in some studies^26–28 or mildly reduced in other studies.^29,30 In DLB^7,25 and PDD,²⁵ heart rate variability has been reported to be reduced, although comparisons of the heart rate variability of patients with DLB/PDD and patients with PD have not been reported thus far. Our results indicate that the cardiac parasympathetic system might be impaired in DLB.

Our patients with Lewy body disorders showed cardiovascular, skin vasomotor, and sudomotor dysfunctions. In particular, impairment of sudomotor function on the palm (so-called emotional sweating) was noticeable. Emotional sweating may be impaired in Lewy body disorders. In addition, autonomic dysfunction was more severe in patients with DLB/PDD than in patients with PD. However, the pattern and severity of autonomic impairments were not different between the patients with DLB and patients with PDD.

It has been suggested that in PD, Lewy body pathology in the autonomic nervous system begins in the brainstem, including the dorsal motor nucleus of the vagal nerves, and progresses to the neocortex.⁴ Our patients with PD did not exhibit prominent abnormality in heart rate variability, but our patients with DLB presented reduced heart rate variability, which may reflect the involvement of dorsal motor nucleus of the vagal nerve. On the other hand, Lewy body pathology is also observed in the raphe,¹³ which plays an important role in the generation of SSwR and SkVR.³¹ Therefore, reduced SSwR and SkVR observed in our patients with Lewy body disorders may be related to the involvement of the raphe. In addition, Lewy body pathology in PD is observed, albeit mild, in the ventrolateral medulla,¹³ which plays an important role in blood pressure control.

Lewy body pathology and neuronal loss in the sympathetic ganglia are observed in Lewy body disorders.³² Cardiac MIBG uptake, which reflects postganglionic sympathetic function, is reduced in patients with Lewy body disorders, and the reduction is more pronounced in patients with DLB than in those with PD.^8,33 Lewy body pathology may also start in the cardiac sympathetic neurons in the early stages of PD.^11,34 Sympathetic dysfunction observed in our patients with Lewy body disorders may reflect postganglionic sympathetic lesions, as well as lesions in the central autonomic nervous system.

Although Lewy body pathology in PD may begin in the brainstem and olfactory nucleus, there may be a different pattern of evolution in DLB, with some studies suggesting that cerebrocortical pathology, including the limbic and neocortical systems, predominates in DLB.^15,35 In some cases, it is known that autonomic failure precedes DLB for several years.^5,6 The autonomic nervous system is regulated by several cerebral regions, including the amygdala, cingulate gyrus, and the insular and frontobasal cortices.³⁶ These limbic lesions play an important role, particularly in so-called emotional sweating,^37,38 which can be clinically investigated by evaluation of SSwR³⁷ or sympathetic skin response.³⁹ Therefore, SSwRs were severely diminished in our patients with Lewy body pathology. In addition, the limbic system participates in cardiovascular regulation. Limbic lesions may explain the severe autonomic dysfunction in our patients with DLB/PDD.

In our study, the clinical severity was somewhat greater in the DLB and PDD groups as compared to that in the PD group, and the disease duration was shorter in the DLB as compared to the other LBD groups. Despite this, we did not find statistically significant differences among the three LBD groups. However, it is not beyond the realm of possibility that differences in disease progression affected our results.

Clinically, sudomotor dysfunction on the palm, which was severe in our patients with DLB, patients with PDD, and patients with PD, may be a sensitive predictor for LBD. Meanwhile, skin vasomotor and cardiovascular dysfunction affected the patients with DLB and patients with PDD to a greater extent when compared to the patients with PD in our study. This finding may reflect an expanded distribution of Lewy body pathology throughout the nervous system. Similarities in autonomic dysfunction between our patients with DLB and patients with PDD indicate a possible uniformity of impairment of the autonomic nervous system in DLB and PDD.