Original Article
Finger Cold-Induced Vasodilatation, Sympathetic
Skin Response, and R–R Interval Variation in
Patients With Progressive Spinal Muscular Atrophy
Hidee Arai, MD; Yuzo Tanabe, MD; Yasuo Hachiya, MD; Eiko Otsuka, MD; Satoko Kumada, MD;
Wakana Furushima, MD; Jun Kohyama, MD; Sumimasa Yamashita, MD; Jun-ichi Takanashi, MD;
Yoichi Kohno, MD
ABSTRACT
To elucidate autonomic function in spinal muscular atrophy, we evaluated finger cold-induced vasodilatation, sympathetic
skin response, and R–R interval variation in 10 patients with spinal muscular atrophy: 7 of type 1, 2 of type 2, and 1 of type
3. Results of finger cold-induced vasodilatation, sympathetic skin response, and R–R interval variation were compared
with those of healthy children. Finger cold-induced vasodilatation was abnormal in 6 of 10patients with spinal muscular
atrophy; it was normal in the healthy children. The mean sympathetic skin response latency and amplitude did not differ
significantly from those of the healthy children. Amplitudes of sympathetic skin response to sound stimulation were absent
or low in all six patients with spinal muscular atrophy. No significant difference was found in the mean R–R interval variation of patients with spinal muscular atrophy and healthy children. Results show that some patients with spinal muscular
atrophy have autonomic dysfunction, especially sympathetic nerve hyperactivity, that resembles dysfunction observed in
amyotrophic lateral sclerosis. (J Child Neurol 2005;20:871–875).
Spinal muscular atrophy engenders loss and degeneration of anterior horn cells in the spinal cord and cranial nerve nuclei. It is classified into three types according to two clinical criteria: the age at
onset and the severity of the muscle weakness. Patients with the
severe form of spinal muscular atrophy (type 1) are never able to
sit unassisted. Progressive respiratory muscle weakness prevents
their survival beyond 2 years of age. The mortality of patients with
Received March 20, 2004. Received revised November 19, 2004. Accepted
for publication December 28, 2004.
From the Department of Pediatrics (Dr Arai), National Hospital Organization,
Chiba Medical Center, Chiba, Japan; Department of Pediatrics (Drs Arai,
Takanashi, and Kohno), Graduate School of Medicine, Chiba University,
Chiba, Japan; Division of Neurology (Dr Tanabe), Chiba Children’s Hospital,
Chiba, Japan; Department of Pediatrics (Drs Hachiya, Otsuka, and Kumada),
Metropolitan Fuchu Medical Center for Severe Motor and Intellectual
Disabilities, Tokyo, Japan; Department of Pediatrics and Developmental
Biology (Drs Furushima and Kohyama), Graduate School of Medicine, Tokyo
Medical and Dental University, Tokyo, Japan; and Division of Pediatric
Neurology (Dr Yamashita), Kanagawa Children’s Medical Center, Yokohama,
Japan.
Address correspondence to Dr Hidee Arai, Department of Pediatrics, National
Hospital Organization, Chiba Medical Center, 4-1-2, Tsubakimori, Cyuouku, Chiba, 260-8606, Japan. Tel: 81-43-251-5311; fax: 81-43-255-1675; e-mail:
[email protected].
spinal muscular atrophy type 1 is improved by use of ventilators
for respiratory failure.1
Circulatory collapse and sudden death have been reported in
patients with amyotrophic lateral sclerosis who manifest autonomic nervous dysfunction.2–6 There have also been studies reporting sudden death7 or fluctuation of blood pressure and heart rate
in patients with spinal muscular atrophy with autonomic failure.8
For that reason, investigation of autonomic function in spinal muscular atrophy is important to improve the quality of life and the prognosis of patients with spinal muscular atrophy. This study assessed
autonomic function in patients with spinal muscular atrophy using
simple and noninvasive neurophysiologic methods.
METHODS
This study examined 10 patients with spinal muscular atrophy, 7 boys and
3 girls, with a mean age of 7.6 ± 4.8 years (range 2–18 years) (Table 1). All
patients fulfilled the diagnostic criteria for spinal muscular atrophy from
the results of muscle biopsies or gene analysis except patient 7, whose siblings were diagnosed as having spinal muscular atrophy type 1 based on clinical and pathologic findings. Nutritional status was good in all patients.
Resting tachycardia was evident in seven patients. Patient 6 had experienced
some cardiocirculatory events, including paroxysmal elevation of blood pressure and tachycardia at awakening.8 No patients had a history of Raynaud
871
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872
Journal of Child Neurology / Volume 20, Number 11, November 2005
Table 1. Clinical Summary of the Patients With Spinal Muscular Atrophy
Type
Age at
Onset
(mo)
Survival
Motoneuron
Gene Deletions
Artificial
Respiratory
Support
M
F
M
1
1
1
<6
5–7
<3
Exon 7/8
Exon 7
Exon 7/8
F
M
M
M
M
F
F
1
1
1
1
2
2
3
1
<3
<3
1
7–8
14–16
14–16
Exon 7/8
Exon 7/8
Exon 7/8
Not done
Exon 7/8
Not done
Exon 7
24 hr
24 hr
Nocturnal nasal
pressure support
24 hr
24 hr
24 hr
24 hr
No
No
No
Age
(yr)
Sex
1
2
3
2
5
5
4
5
6
7
8
9
10
6
6
8
18
6
14
6
Patient
Motor
Function
Hyperhidrosis
Resting
Heart
Rate (min)
Unable to sit
Unable to sit
Unable to sit
Yes
Yes
Yes
70–85
100–110
120
Unable to sit
Unable to sit
Unable to sit
Unable to sit
Able to sit
Able to sit
Able to walk
Yes
No
Yes
Yes
No
Yes
No
100–120
100–120
100–120
100–110
80–90
112
86
phenomenon. Patient 9 had experienced peripheral coldness of the hands
R–R Interval of Variation
and feet. Seven patients experienced hyperhidrosis on their palms at rest.
According to the previously described method,15 R–R interval variation of
The control subjects for this study were 17 healthy children, 8 boys and
100 sweeps of the electrocardiograph was obtained at rest and R–R inter-
9 girls, with a mean age of 9.2 ± 3.2 years (range 5–15 years).
val was measured in the supine position. The mean R–R interval was an
Finger cold-induced vasodilatation and sympathetic skin response were
average of the longest and shortest R–R intervals. The range of the R–R
examined in all subjects. Subjects were placed comfortably in a quiet room
interval was the difference between them. The R–R interval variation was
at 23 to 27°C and were tested awake in a sitting position, except for the
defined as a percentage of the average interval using the following formula:
patients with spinal muscular atrophy, who were not able to sit. All stud-
R–R interval variation = range of R–R interval/mean R–R interval 100.
ies were performed at least 2 hours after meals. One physician (H.A.) tested
Normal values of finger cold-induced vasodilatation, sympathetic skin
finger cold-induced vasodilatation and the sympathetic skin response of all
response, and R–R interval variation were obtained from the 17 healthy con-
patients. The results of finger cold-induced vasodilatation in control sub-
trol subjects.
jects were analyzed statistically. Existence of a normal distribution was confirmed. The Mann-Whitney U-test was used to analyze qualitative differences
RESULTS
between the control subjects and the patients with spinal muscular atrophy. Informed consent was obtained from all participants or their parents.
Cold-Induced Vasodilatation
According to a previously described method,9–11 the skin temperature on the
tip of the right index finger was measured every 30 seconds with a thermometer (YSI precision 4000A, Yellow Springs Instrument Inc., Yellow
Springs, Ohio) that was sufficiently accurate to measure to 0.02°C. A temperature sensor was attached on the inner side of the finger with an insulation pad using adhesive tape. After a 5-minute pretesting period, the
finger was immersed in ice water to the distal phalanx for 15 minutes. At
the end of the immersion period, the finger was removed from the ice
water, dried with a towel, and allowed to recover for 10 minutes. The ice
water temperature was below 0.5°C. Table 2 shows the selected indices.
Sympathetic Skin Responses
Sympathetic skin responses were performed by the previously described
method.12–14 A standard electromyographic active disk electrode was attached
to the palm; a reference electrode was attached to the dorsum of the hand.
An electromyograph (Neuropack, Nihon Kohden Corp., Tokyo, Japan)12–14
was used with a filter setting of a 0.5 to 1000 Hz bandpass. Sympathetic skin
responses were examined using two kinds of stimuli. The sound stimulus,
a clicking sound of 100 dB intensity, was delivered to both ears by headphones. The electric stimulus was delivered as square-wave electric pulses
of 0.2-millisecond duration and 4 to 10 mA intensity on the median nerve
at the right wrist. Patient 2 was stimulated at the left wrist because of her
physical condition. Sympathetic skin responses were performed with both
stimuli in six patients with spinal muscular atrophy and with electric stimulus alone in the other patients. Both stimuli were delivered at irregular intervals more than 10 times. Five waves showing the highest amplitudes were
selected; their latencies were measured.
Regarding finger cold-induced vasodilatation, no significant differences were found between the patients with spinal muscular atrophy and control subjects for skin temperature before immersion,
lowest temperature during immersion, highest temperature during
immersion, or skin temperature 5 minutes after removal from the
ice water (see Table 2). The measured change in skin temperature
before immersion to 5 minutes after removal from the ice water
was significantly different (P < .05) between the patients with
spinal muscular atrophy and the control subjects. Hunting reactions
were recognized in all control subjects but in only 6 of 10 patients
with spinal muscular atrophy. Patients 4, 6, 7, and 9 showed no hunting reaction. The skin temperature of patient 3 was not lowered
sufficiently during immersion. The skin temperature 5 minutes
after removal from ice water of patients 6, 7, and 9, as well as the
lowest temperature during immersion of patients 7, 8, and 9, was
lower than 2 SD of the control subjects.
Regarding sympathetic skin response to electrical stimuli,
no significant differences in mean latencies and amplitudes were
observed between the patients with spinal muscular atrophy
and the control subjects (Table 3). Patients 1 and 7 demonstrated no sympathetic skin response to sound stimuli. In contrast, all of the control subjects responded. The amplitudes of
sympathetic skin response to sound stimuli were significantly
lower (P < .05) in the patients with spinal muscular atrophy
than in the control subjects.
No significant difference was found in the mean R–R interval
variation between the patients with spinal muscular atrophy and
the control subjects.
Table 4 summarizes the results of examinations of the autonomic nervous system in the patients with spinal muscular atrophy.
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Vasodilatation, Skin Response, and R–R Interval in Progressive Spinal Muscular Atrophy / Arai et al
873
Table 2. Result of Finger Cold-Induced Vasodilatation
Patient
1
2
3
4
5
6
7
8
9
10
Mean ± SD
Healthy children (n)
Mean ± SD
T pre (°C)
T min (°C)
36.20
34.70
36.52
36.08
36.10
34.76
34.96
35.66
26.70
33.84
34.55 ± 2.89
10
34.70 ± 0.84
8.10
8.34
27.00
7.20
13.96
7.74
3.38
4.26
1.80
10.96
8.62 ± 5.67
10
11.45 ± 3.12
T max (°C)
30.94
13.46
29.82
10.84
18.02
15.50
13.44
24.20
9.08
25.84
19.58 ± 7.80
10
21.23 ± 3.97
T(°C)
T rec (°C)
35.14
34.46
35.28
35.10
35.34
24.38
28.18
35.40
31.66
33.48
32.84 ± 3.75
10
34.45 ± 0.82
1.06
0.24
1.24
0.98
0.76
10.38
6.78
0.26
4.96
0.36
2.70 ± 3.49*
10
0.54 ± 0.37
T max = the highest skin temperature during immersion; T min = the lowest skin temperature during immersion; T pre = skin temperature just before immersion; T rec = the skin
temperature 5 minutes after removal from ice water; T = change from T pre to T rec.
*P < .05 versus healthy children.
The skin temperature of patient 9 was significantly lower
than that of the control subjects (2 SD) before immersion, with
no hunting reaction. In addition, that patient’s skin temperature after
immersion was much higher than before immersion. The patient
felt a flushing sensation on her right index finger.
DISCUSSION
This study used simple and noninvasive methods that required
neither special machines nor techniques. Hunting reaction describes
the phenomenon by which the skin temperature falls soon after ice
water immersion and starts to increase only after a few minutes
in finger cold-induced vasodilatation.9 Vasoconstriction at the fingertip is controlled solely by the sympathetic nerve activity.
Microneurography confirmed that a decrease in skin temperature
in response to a cold stimulus reflects sympathetic nerve hyperactivity.10 In idiopathic palmoplantar hyperhidrosis with sympathetic
hyperactivity, the lowest temperature during immersion is normal or decreased; the hunting reaction and skin temperature 5 minutes after removal from ice water are poor.11 In contrast, patients
with Shy-Drager syndrome, cervical spondylosis, and cervical disk
herniation who have pathologic changes in the sympathetic nerve
show an incomplete decrease in the lowest temperature during
immersion. They particularly display an absence of the acute
decrease soon after immersion.10 Therefore, finger cold-induced
vasodilatation is a simple and useful method for the screening of
skin vasomotor sympathetic nerve functions.
Finger cold-induced vasodilatation in this study showed an
increase in sympathetic activity in four patients with spinal muscular atrophy and a decrease in two (Figure 1). Three of six patients
who showed an abnormal finger cold-induced vasodilatation
response also exhibited an abnormal R–R interval variation. These
results suggest that patients with spinal muscular atrophy have an
imbalance in sympathetic and parasympathetic nervous functions.
Sympathetic skin response has been proposed as a simple and
noninvasive approach to investigate sudomotor sympathetic nerve
function. The patients with spinal muscular atrophy showed no
response or low amplitude in the sympathetic skin response with
sound stimuli, whereas all control subjects showed normal amplitude. These findings suggest an abnormality of sudomotor function
in spinal muscular atrophy. Furthermore, sympathetic hyperactivity
in finger cold-induced vasodilatation might account for hyperhidrosis on the palm, which is commonly recognized in patients with
spinal muscular atrophy.
Table 3. Result of Sympathetic Skin Response
Electric Stimulation
Mean Amplitude (V)
Mean Latency (ms)
Left
Right
Left
Right
1253.0 ± 276.6
1004.0 ± 102.2
921.0 ± 253.0
1100.0 ± 187.2
1286.0 ± 124.7
1240.0 ± 103.7
1412.0 ± 90.9
1292.0 ± 164.8
1498.0 ± 87.6
1286.0 ± 74.3
1235.0 ± 217.7
2.79 ± 1.38
2.48 ± 0.84
12.53 ± 3.09
2.07 ± 0.52
1.17 ± 0.76
3.18 ± 1.18
1.83 ± 0.84
5.79 ± 1.78
14.72 ± 4.17
7.19 ± 3.93
2.18 ± 0.86
1.89 ± 1.03
2.56 ± 0.73
9.18 ± 2.18
2.35 ± 0.83
1.66 ± 0.66
2.22 ± 0.42
0.58 ± 0.30
6.71 ± 1.92
9.24 ± 2.14
6.86 ± 2.14
2.50 ± 1.40
12
12
12
1353.2 ± 101.2
3.49 ± 1.95
3.43 ± 2.06
Mean Latency (ms)
Patient
Right
1
1082.0 ± 246.5
2
1010.0 ± 107.1
3
875.0 ± 220.1
4
1090.0 ± 129.2
5
1369.0 ± 100.9
6
1194.0 ± 89.6
7
1507.0 ± 138.8
8
1301.0 ± 155.3
9
1458.0 ± 121.5
10
1310.0 ± 89.9
Mean
1281.6 ± 253.4
± SD
Healthy
12
children (n)
Mean
1323.3 ± 111.4
± SD
Sound Stimulation
Left
No response
No response
Not done
Not done
Not done
Not done
Not done
Not done
2220.0 ± 201.8 2216.7 ± 274.9
Not done
Not done
No response
No response
1317.0 ± 145.7 1394.0 ± 134.7
Not done
Not done
1590.0 ± 63.5 1580.0 ± 82.2
1453.5 ± 193.0 1487.0 ± 131.5
11
11
1466.1 ± 140.8 1475.7 ± 128.5
*P < .05 versus healthy children.
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Mean Amplitude (V)
Right
Left
No response
Not done
Not done
Not done
0.64 ± 0.20
Not done
No response
0.96 ± 0.20
Not done
0.71 ± 0.42
0.84 ± 0.18*
No response
Not done
Not done
Not done
0.71 ± 0.32
Not done
No response
1.21 ± 0.21
Not done
0.46 ± 0.27
0.84 ± 0.53*
11
11
2.69 ± 2.60
2.56 ± 2.16
874
Journal of Child Neurology / Volume 20, Number 11, November 2005
Figure 1. Finger cold-induced vasodilatation. A, solid line indicates normal, healthy
child. Broken lines indicate patients 4, 6, 7, and
9 who had an increased sympathetic nerve
activity. B, solid line indicates normal healthy
child. Broken lines indicate patients 3 and 5
who had a decreased sympathetic nerve
activity.
Various autonomic dysfunctions have been found in amyotrophic lateral sclerosis, especially sympathetic nerve hyperactivity.16–18 These dysfunctions include an imbalance between the
sympathetic and the parasympathetic nerves19; decreased R–R
interval variation, suggesting an impairment in the sympathovagal
balance20; sudomotor sympathetic nerve dysfunction21; and absence
of response or low amplitude and increased latencies of sympathetic
skin response that are attributable to sympathetic nerve dysfunction.13,14 Therefore, it is inferred that amyotrophic lateral sclerosis
is associated with several autonomic dysfunctions, such as sympathetic nerve hyperactivity and an imbalance between the sympathetic and the parasympathetic nerves.
The pathology of the autonomic nervous system in amyotrophic lateral sclerosis has been investigated in both the brain
and the spinal cord. Atrophy of the intermediolateral nucleus,
which is an efferent pathway of the sympathetic nerve, has been
demonstrated in amyotrophic lateral sclerosis.22 Some studies
have shown gliosis in the globus pallidus, amygdala, lateral hypothalamic area, and medial cortex of the temporal tip.2,23 Nevertheless,
the pathophysiology of the autonomic dysfunction in amyotrophic
lateral sclerosis remains virtually unknown.
A few neuropathologic studies exist concerning the autonomic nervous system in spinal muscular atrophy. The intermediolateral nucleus has been reported to be almost spared,24 whereas
degeneration of the anterior roots of the spinal cord, hypothalamus,
and posterior roots in spinal muscular atrophy has been
observed.25,26 In addition, studies have described altered synapse
formation on the motoneuron and a disturbed neuron-glia relationship. Moreover, a report of prolonged latencies in electrophysiologic examinations, such as visual evoked potentials,
brainstem evoked responses, and somatosensory evoked potentials
in spinal muscular atrophy types 1 and 2, has suggested the involvement of the central nervous system.7
It remains unclear whether the autonomic functions in spinal
muscular atrophy are primarily disordered. In amyotrophic lateral
sclerosis, the autonomic function is inferred to be influenced by
physiologic factors, such as a long-term bedridden state, severe muscle atrophy, and stress under a long-term artificial respiratory support.2 In contrast, based on an analysis of heart rate variability in
patients with Duchenne-type progressive muscular dystrophy who
had autonomic dysfunction including higher both sympathetic and
parasympathetic activity in adults and decrease in parasympathetic activity without increase in sympathetic activity in children,
it was concluded that the autonomic dysfunction was not secondary to cardiopulmonary involvement.27,28
One study of the ontogenesis of the aortic baroreflex in experimental animals showed that the excitability of the aortic baroreflex decreases under conditions of microgravity, proving that gravity
is essential for baroreflex development.29 Another study indicated
an increase in muscle sympathetic nerve activity and a decrease in
Table 4. Summary of Autonomic Examinations in Spinal Muscular Atrophy
Patient
1
2
3
4
5
6
7
8
9
10
CIVD
SSRe
SSRs
RRIV
Normal
Normal
Hypoactivity
Hyperactivity
Hypoactivity
Hyperactivity
Hyperactivity
Normal
Hyperactivity
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
No response
Not done
Not done
Not done
Low amplitude
Not done
No response
Low amplitude
Not done
Low amplitude
↑
Normal
Normal
↓
↑
↓
Normal
Not done
Normal
↑
CIVD = finger cold-induced vasodilatation. Hyperactivity is defined as when skin temperature just before immersion is normal or decreased, the lowest skin temperature during
immersion is normal, the highest skin temperature during immersion is decreased, the skin temperature 5 minutes after removal from ice water is normal or decreased, and
there is a lack of a hunting reaction. Hypoactivity is defined as when the skin temperature just before immersion is normal, the lowest skin temperature during immersion is
increased, the highest skin temperature during immersion and the skin temperature 5 minutes after removal from ice water are normal, and there is a positive hunting reaction;
RRIV = R-R interval variation; SSRe = sympathetic skin response to electric stimulus; SSRs = sympathetic skin response to sound stimulus; ↑= higher than healthy children; ↓ =
lower than healthy children.
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Vasodilatation, Skin Response, and R–R Interval in Progressive Spinal Muscular Atrophy / Arai et al
R–R interval variation after 120 days of head-down bed rest.30
Patients with spinal muscular atrophy, especially type 1, can hardly
experience bodily movements against gravity within the first
6 months because of severe generalized muscle weakness and
hypotonia. Consequently, these patients, who are forced to be
bedridden from infancy, are likely to experience autonomic dysfunction and severe neurodegenerative or skeletal muscle disease.
In conclusion, the results of this study reveal both vasomotor and sudomotor autonomic dysfunctions in spinal muscular
atrophy. Autonomic dysfunctions can directly affect the quality of
life and the life expectancy of patients with spinal muscular atrophy.2 Therefore, autonomic nerve function should be evaluated in
the management of patients with spinal muscular atrophy with ventilator support. A pressing need exists for further investigation of
the treatment of autonomic nerve dysfunction in spinal muscular
atrophy.
Acknowledgment
We are grateful to Dr M. Kijima (Department of Neurology, National Hospital Organization, Chiba Medical Center) for valuable advice concerning finger coldinduced vasodilatation.
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